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Abstract:

The invention relates to pyridinyl nicotinic acetylcholine receptor
ligands, compositions comprising an effective amount of a pyridinyl
nicotinic acetylcholine receptor ligand and methods to treat or prevent a
condition, such as depression and nicotine dependence, comprising
administering to an animal in need thereof an effective amount of a
pyridinyl nicotinic acetylcholine receptor ligand.

Claims:

1. A compound of formula I: ##STR00424## wherein R1 is hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, allyl, or C3-C6 cycloalkyl; R2, R3 and R4
are each independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl, C3-C6 cycloalkyl or
C1-C6 alkyl substituted with one or more fluorine atoms; Y is a
bond, or --(CH2)q--, optionally substituted with one or two
groups independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl; Z is cyclopropyl, and wherein said cyclopropyl is optionally
substituted with one or two C1-C3 alkyl groups; R5 is
C1-C6 straight chain alkyl; C3-C6 branched chain
alkyl; C1-C6 hydroxyalkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; arylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; arylalkoxy in which the alkoxy portion
contains from 1 to 6 carbon atoms; aryl; biaryl; heteroarylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; heteroarylalkoxy in
which the alkoxy portion contains from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl;
--(CH2)1-6--O--(CH2)0-6-heteroaryl;
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl;
heteroaryl; or a four- to six-membered saturated heterocycle, with the
proviso that R5 is not arylalkoxy or heteroarylalkoxy when Z is
C3-cycloalkyl; wherein R5 is optionally substituted with one or
two substituents independently selected from C1-C6 straight
chain alkyl; C3-C6 branched chain alkyl; C1-C6
fluoroalkyl; C1-C6 hydroxyalkyl; aryloxy; heteroaryloxy;
C3-C6 cycloalkyloxy; C1-C6 alkoxy; alkoxyalkyl in
which the alkoxy and alkyl portions each independently contain from 1 to
6 carbon atoms; alkoxyalkoxy in which the alkoxy portions each
independently contain from 1 to 6 carbon atoms; F; --OH; --NH2;
C1-C6 alkylthio; --CF3; C1-C6 monoalkylamino;
C1-C6 dialkylamino; carboxyl; and C2-C6
alkoxycarbonyl; and wherein if R5 comprises an aryl group or a
heteroaryl group, then R5 is optionally substituted with one or two
substituents selected from C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; C1-C6 fluoroalkyl;
C1-C6 hydroxyalkyl; C1-C6 alkoxy; alkoxyalkyl in
which the alkoxy and alkyl portions each independently contain from 1 to
6 carbon atoms; alkoxyalkoxy in which the alkoxy portions each
independently contain from 1 to 6 carbon atoms; F; --OH; --NH2;
C1-C6 alkylthio; --CF3; C1-C6 monoalkylamino;
C1-C6 dialkylamino; carboxyl; C2-C6 alkoxycarbonyl;
Cl and OCF3; or R5 is --(CH2)rNRvRvi;
--(CH2)rC(O)NRvRvi; --(CH2)rC(O)ORix;
--(CH2)rSRviii; --(CH2)rSO2Rix or
--(CH2)rSORix; wherein: Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; C3-C6 cycloalkyl; aryl;
arylalkyl in which the alkyl portion contains 1 to 6 carbon atoms;
--(CO)Rvii; --(CO)ORvii; --SO2Rvii; or Rv and
Rvi form a four- to six-membered saturated heterocyclic ring having
a single nitrogen atom; wherein if one of Rv and Rvi is
--(CO)Rvii or --SO2Rvii, the other is not --(CO)Rvii
or --SO2Rvii; Rvii is C1-C6 straight chain alkyl
which is optionally substituted with one or two hydroxyl groups;
C3-C6 branched chain alkyl which is optionally substituted with
one or two hydroxyl groups; C3-C6 cycloalkyl, wherein when the
cycloalkyl group contains more than 3 carbon atoms, it is optionally
substituted with one or two hydroxyl groups; aryl which is optionally
substituted with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl
group and one fluorine atom, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl, and
wherein if the C1-C6 straight chain alkyl group, the
C3-C6 branched chain alkyl group or the C3-C6
cycloalkyl group is substituted, then no more than one heteroatom
selected from the oxygen atom in the hydroxyl group and the sulfur atom
in --SO2Rvii is bound to any single carbon atom; arylalkyl in
which the alkyl portion contains from 1 to 6 carbon atoms; heteroaryl; or
heteroarylalkyl in which the alkyl portion contains from 1 to 6 carbon
atoms; or when Rv is not H and Rvi is either --(CO)Rvii or
--SO2Rvii, Rv and Rvii can be taken together to form
a 4- to 7-membered ring; Rviii is hydrogen, C1-C6 straight
chain alkyl optionally substituted with one or two hydroxyl groups or
C1-C6 alkoxy groups, wherein if the C1-C6 straight
chain alkyl group is substituted, then no more than one heteroatom
selected from the oxygen atom in the hydroxyl group, the oxygen atom in
the alkoxy group and the sulfur atom in --(CH2)rSRviii is
bound to any single carbon atom; C3-C6 branched chain alkyl;
C3-C6 cycloalkyl; aryl that is optionally substituted with 1 or
2 fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; or Rviii is C(O)Rx;
Rix is C1-C6 straight chain alkyl optionally substituted
with one or two hydroxyl groups or C1-C6 alkoxy groups, wherein
if the C1-C6 straight chain alkyl group is substituted, then no
more than one heteroatom selected from the oxygen atom in the hydroxyl
group, the oxygen atom in the alkoxy group and the sulfur atom in
--(CH2)rSO2Rix is bound to any single carbon atom;
C3-C6 branched chain alkyl; C3-C6 cycloalkyl; aryl
that is optionally substituted with 1 or 2 fluorine atoms, one hydroxyl
group, one hydroxyl group and one fluorine atom, or C1-C6
hydroxyalkyl; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, one hydroxyl group and one fluorine
atom, or C1-C6 hydroxyalkyl, wherein the number of substituents
does not exceed the number of available C--H and N--H bonds; or arylalkyl
in which the alkyl portion contains from 1 to 6 carbon atoms and the aryl
portion is optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl; Rx is C1-C6 straight chain
alkyl optionally substituted with one or two hydroxyl groups or
C1-C6 alkoxy groups, wherein if the C1-C6 alkyl group
is substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group and the oxygen atom in the alkoxy group is
bound to any single carbon atom; C3-C6 branched chain alkyl;
C3-C6 cycloalkyl; aryl that is optionally substituted with 1 or
2 fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; arylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms and in which the aryl portion is optionally substituted with
1 or 2 fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; C1-C6 monoalkylamino;
or C1-C6 dialkylamino; wherein if R5 contains at least one
saturated carbon atom and said R5 is substituted with two
substituents independently selected from C1-C6 alkoxy,
alkoxyalkoxy in which the alkoxy portions each independently contain from
1 to 6 carbon atoms, F, --OH, --NH2, C1-C6 monoalkylamino,
C1-C6 dialkylamino, and C1-C6 alkylthio, then said
two substituents are not bound to the same saturated carbon atom; m is 2;
n is an integer ranging from 1 to 2; p is an integer ranging from 0 to 2;
wherein when n is 2 or p is 2, the carbon atom linked to the oxygen atom
can be substituted with a C1-C6 straight chain alkyl group or a
C3-C6 branched chain alkyl group; q is an integer ranging from
1 to 5; r is an integer ranging from 0 to 5; and pharmaceutically
acceptable derivatives thereof.

2. A compound of formula I: ##STR00425## wherein R1 is hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, allyl, or C3-C6 cycloalkyl; R2, R3 and R4
are each independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl, C3-C6 cycloalkyl or
C1-C6 alkyl substituted with one or more fluorine atoms; Y is a
bond, or --(CH2)q--, optionally substituted with one or two
groups independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl; Z is cyclopropyl, and wherein said cyclopropyl is optionally
substituted with C1-C3 alkyl; R5 is C1-C6
straight chain alkyl; C3-C6 branched chain alkyl;
C1-C6 hydroxyalkyl; alkoxyalkyl in which the alkoxy and alkyl
portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; arylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; arylalkoxy in which the alkoxy portion
contains from 1 to 6 carbon atoms, with the proviso that R5 is not
arylalkoxy when Z is C3-cycloalkyl; aryl; biaryl; heteroarylalkyl in
which the alkyl portion contains from 1 to 6 carbon atoms;
heteroarylalkoxy in which the alkoxy portion contains from 1 to 6 carbon
atoms; --(CH2)1-6--O--(CH2)0-6-aryl;
--(CH2)1-6--O--(CH2)0-6-heteroaryl;
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl;
heteroaryl; or four- to six-membered saturated heterocycle; wherein
R5 is optionally substituted with one or two substituents
independently selected from C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; C1-C6 fluoroalkyl;
C1-C6 hydroxyalkyl; aryloxy; heteroaryloxy; C3-C6
cycloalkyloxy; C1-C6 alkoxy; alkoxyalkyl in which the alkoxy
and alkyl portions each independently contain from 1 to 6 carbon atoms;
alkoxyalkoxy in which the alkoxy portions each independently contain from
1 to 6 carbon atoms; F; --OH; --NH2; C1-C6 alkylthio;
--CF3; C1-C6 monoalkylamino; C1-C6 dialkylamino;
carboxyl; and C2-C6 alkoxycarbonyl; and wherein if R5
comprises an aryl group or a heteroaryl group, then R5 is optionally
substituted with one or two substituents selected from C1-C6
straight chain alkyl; C3-C6 branched chain alkyl;
C1-C6 fluoroalkyl; C1-C6 hydroxyalkyl;
C1-C6 alkoxy; alkoxyalkyl in which the alkoxy and alkyl
portions each independently contain from 1 to 6 carbon atoms;
alkoxyalkoxy in which the alkoxy portions each independently contain from
1 to 6 carbon atoms; F; --OH; --NH2; C1-C6 alkylthio;
--CF3; C1-C6 monoalkylamino; C1-C6 dialkylamino;
carboxyl; C2-C6 alkoxycarbonyl; Cl and OCF3; or R5 is
--(CH2)rNRvRvi;
--(CH2)rC(O)NRvRvi; --(CH2)rC(O)ORix;
--(CH2)rSRviii; --(CH2)rSO2Rix or
--(CH2)rSORix; wherein: Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; C3-C6 cycloalkyl; aryl;
arylalkyl in which the alkyl portion contains 1 to 6 carbon atoms;
--(CO)Rvii; --(CO)ORvii; --SO2Rvii; or Rv and
Rvi form a four- to six-membered saturated heterocyclic ring having
a single nitrogen atom; wherein if one of Rv and Rvi is
--(CO)Rvii or --SO2Rvii, the other is not --(CO)Rvii
or --SO2Rvii; Rvii is C1-C6 straight chain alkyl
which is optionally substituted with one or two hydroxyl groups;
C3-C6 branched chain alkyl which is optionally substituted with
one or two hydroxyl groups; C3-C6 cycloalkyl, wherein when the
cycloalkyl group contains more than 3 carbon atoms, it is optionally
substituted with one or two hydroxyl groups; aryl which is optionally
substituted with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl
group and one fluorine atom, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl, and
wherein if the C1-C6 straight chain alkyl group, the
C3-C6 branched chain alkyl group or the C3-C6
cycloalkyl group is substituted, then no more than one heteroatom
selected from the oxygen atom in the hydroxyl group and the sulfur atom
in --SO2Rvii is bound to any single carbon atom; arylalkyl in
which the alkyl portion contains from 1 to 6 carbon atoms; heteroaryl; or
heteroarylalkyl in which the alkyl portion contains from 1 to 6 carbon
atoms; or when Rv is not H and Rvi is either --(CO)Rvii or
--SO2Rvii, Rv and Rvii can be taken together to form
a 4- to 7-membered ring; Rviii is hydrogen, C1-C6 straight
chain alkyl optionally substituted with one or two hydroxyl groups or
C1-C6 alkoxy groups, wherein if the C1-C6 straight
chain alkyl group is substituted, then no more than one heteroatom
selected from the oxygen atom in the hydroxyl group, the oxygen atom in
the alkoxy group and the sulfur atom in --(CH2)rSRviii is
bound to any single carbon atom; C3-C6 branched chain alkyl;
C3-C6 cycloalkyl; aryl that is optionally substituted with 1 or
2 fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; or Rviii is --C(O)Rx;
Rix is C1-C6 straight chain alkyl optionally substituted
with one or two hydroxyl groups or C1-C6 alkoxy groups, wherein
if the C1-C6 straight chain alkyl group is substituted, then no
more than one heteroatom selected from the oxygen atom in the hydroxyl
group, the oxygen atom in the alkoxy group and the sulfur atom in
--(CH2)rSO2Rix is bound to any single carbon atom;
C3-C6 branched chain alkyl; C3-C6 cycloalkyl; aryl
that is optionally substituted with 1 or 2 fluorine atoms, one hydroxyl
group, one hydroxyl group and one fluorine atom, or C1-C6
hydroxyalkyl; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, one hydroxyl group and one fluorine
atom, or C1-C6 hydroxyalkyl, wherein the number of substituents
does not exceed the number of available C--H and N--H bonds; or arylalkyl
in which the alkyl portion contains from 1 to 6 carbon atoms and the aryl
portion is optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl; Rx is C1-C6 straight chain
alkyl optionally substituted with one or two hydroxyl groups or
C1-C6 alkoxy groups, wherein if the C1-C6 alkyl group
is substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group and the oxygen atom in the alkoxy group is
bound to any single carbon atom; C3-C6 branched chain alkyl;
C3-C6 cycloalkyl; aryl that is optionally substituted with 1 or
2 fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; arylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms and in which the aryl portion is optionally substituted with
1 or 2 fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; C1-C6 monoalkylamino;
or C1-C6 dialkylamino; wherein if R5 contains at least one
saturated carbon atom and said R5 is substituted with two
substituents independently selected from C1-C6 alkoxy,
alkoxyalkoxy in which the alkoxy portions each independently contain from
1 to 6 carbon atoms, F, --OH, --NH2, C1-C6 monoalkylamino,
C1-C6 dialkylamino, and C1-C6 alkylthio, then said
two substituents are not bound to the same saturated carbon atom; m is 2;
n is an integer ranging from 1 to 2; p is an integer ranging from 0 to 2;
wherein when n is 2 or p is 2, the carbon atom linked to the oxygen atom
can be substituted with a C1-C6 straight chain alkyl group or a
C3-C6 branched chain alkyl group; q is an integer ranging from
1 to 5; r is an integer ranging from 0 to 5; and pharmaceutically
acceptable derivatives thereof; and with the proviso that when Y is a
bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
wherein Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl; --(CH2)rSRviii when
Rviii is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;
--(CH2)rSO2Rix, --(CH2)rSORix or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, C3-C6
cycloalkyl or phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms.

3. The compounds of claim 1, wherein Z is a 1,2-disubstituted cyclopropyl
ring and R5 is C1-C6 hydroxyalkyl.

4. The compounds of claim 1, wherein Y is a bond.

5. The compounds of claim 1, wherein Z is a 1,2-disubstituted cyclopropyl
group.

6. The compounds of claim 1, wherein R5 is C1-C6
hydroxyalkyl.

7. The compounds of claim 1, wherein Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is C1-C6
hydroxyalkyl.

8. The compounds of claim 1, wherein Y is --CH2--, Z is a
1,2-disubstituted cyclopropyl ring and R5 is CH2OH.

9. The compounds of claim 1, wherein Y is --(CH2)2--, Z is a
1,2-disubstituted cyclopropyl ring and R5 is --(CH2)2OH.

10. The compounds of claim 1, wherein Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2CH2OH.

11. The compounds of claim 1, wherein Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is C1-C6 fluoroalkyl.

12. The compounds of claim 1, wherein Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2CH2F.

13. The compounds of claim 1, wherein Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring, and R5 is --CH2OCH3,
--CH2CH2OCH3 or --CH2CH2OCH2CF.sub.3.

14. The compounds of claim 1, wherein Y is a bond, n is 1, p is 0,
R1, R2, R3, and R4 are each hydrogen, Z is a
1,2-disubstituted cyclopropyl ring, and R5 is C1-C6
hydroxyalkyl.

15. The compounds of claim 1, wherein Y is a bond, n is 1, p is 0,
R1, R2, R3, and R4 are each hydrogen, Z is a
1,2-disubstituted cyclopropyl ring, and R5 is alkoxyalkyl in which
the alkoxy and the alkyl portions each independently contain from 1 to 6
carbon atoms and said alkoxyalkyl is optionally substituted with one or
two substituents independently selected from C1-C6 straight
chain alkyl; C3-C6 branched chain alkyl; C1-C6
fluoroalkyl; C1-C6 hydroxyalkyl; aryloxy; heteroaryloxy;
C3-C6 cycloalkyloxy; C1-C6 alkoxy; alkoxyalkyl in
which the alkoxy and alkyl portions each independently contain from 1 to
6 carbon atoms; alkoxyalkoxy in which the alkoxy portions each
independently contain from 1 to 6 carbon atoms; F; --OH; --NH2;
C1-C6 alkylthio; --CF3; C1-C6 monoalkylamino;
C1-C6 dialkylamino; carboxyl; and C2-C6
alkoxycarbonyl.

16. The compounds of claim 1, wherein Y is a bond, n is 1, p is 0,
R1, R2, R3, and R4 are each hydrogen, Z is a
1,2-disubstituted cyclopropyl ring, and R5 is --CH2CH2OH.

17. The compounds of claim 1, wherein Y is a bond, R1 is
C1-C6 alkyl, and R5 is selected from the group consisting
of C1-C6 hydroxyalkyl and C1-C6 alkoxyalkyl.

Description:

[0001] This application is a division of U.S. patent application Ser. No.
12/578,020, filed Oct. 13, 2009, which claims the benefit of priority of
U.S. provisional application No. 61/105,167, filed Oct. 14, 2008, the
disclosure of which is hereby incorporated by reference as if written
herein in its entirety.

FIELD OF THE INVENTION

[0003] The present invention relates to pyridinyl compounds that bind to
nicotinic acetylcholine receptors, compositions comprising an effective
amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods
for treating or preventing a neurological or psychiatric condition or for
aiding smoking cessation, comprising administering to an animal in need
thereof an effective amount of a pyridinyl nicotinic acetylcholine
receptor ligand.

BACKGROUND OF THE INVENTION

[0004] Nicotinic acetylcholine receptors ("nAChRs") are ligand-gated ion
channels found in cell plasma membranes in various tissues, including
skeletal muscle at the neuromuscular junction, the peripheral nervous
system, and the central nervous system. Nicotinic ligands have
traditionally been classified as agonists (or partial agonists) that
activate channel function, or competitive or noncompetitive antagonists,
that block channel function. Ligands such as acetylcholine and nicotine
are agonists, which act by binding to and effecting opening of nAChRs,
and allowing the influx of cations into a cell to produce an excitatory
response. nAChRs can also exist in a desensitized state, in which channel
function is blocked in the presence of an agonist. Chronic nicotine
exposure is associated with desensitization and inactivation of nAChRs.

[0005] nAChRs are potential therapeutic targets for the treatment of
central and peripheral nervous system disorders, including
neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's
disease), age-related or disease-related cognitive impairment,
dyskinesias, Tourette's syndrome, schizophrenia, attention-deficit
hyperactivity disorder, depression, anxiety, mood disorders, pain, and
methamphetamine addiction. In addition, nAChRs are the biological
substrate through which nicotine acts in the body. Studies have shown
that tobacco use is driven by nicotine addiction, in part because of
nicotine's beneficial effects on cerebral functions, such as stabilizing
mood and emotion and producing pro-cognitive and pro-attentive effects.
Epidemiological studies have shown that people with cognitive or mood
disorders are often nicotine dependents, which strongly suggests that
nicotine use is a form of self-medication to treat such disorders. Thus,
nAChRs are potential targets for treating or preventing nicotine
addiction. Moreover, nicotinic acetylcholine receptors in the brain are
thought to play a role not only in cholinergic neurotransmission at
selected loci, but more globally in the modulation of neurotransmission
by other chemical messengers (e.g., dopamine, norepinephrine or
serotonin), and therefore, may play a role in central and peripheral
nervous system disorders that do not result directly from irregularities
in cholinergic neurotransmission.

[0006] Nicotinic acetylcholine receptor channels exist as a family of
subtypes, and each subtype is composed of a homo- or hetero-pentamer of
protein subunits encoded by one of 16 mammalian genes. Each nAChR subtype
has a distinctive biophysical, physiological and pharmacological
signature. In addition, each nAChR subtype has a unique tissue, regional,
cellular and subcellular localization pattern. For example, the
predominant nAChR subtype in the central nervous system is the
α4β2 subtype, which is composed of α4 and β2
protein subunits that are known to assemble in a 2:3 ratio. The
α4β2 nAChR binds nicotine with high affinity.

[0007] The discovery of the subunit composition, characteristics and
localization patterns of particular nAChR subtypes presents an
opportunity in drug discovery for novel compounds that can be
administered to treat central and peripheral nervous system disorders, or
to aid in smoking cessation, by selectively modulating the activity of
particular receptor subtypes found predominantly in the targeted tissues.
Subtype-selective drugs also have the potential to reduce side effects,
and to be critical tools to help identify and distinguish functions and
responses mediated by particular receptor subtypes.

[0008] The publication "Neuronal nicotinic acetylcholine receptors as
targets for drug discovery," of Holladay et al. (J. Med. Chem.
40(26):4169-4194 (1997)) describes the characteristics of different nAChR
subtypes and discusses the potential development of selective agonists
and antagonists of nAChRs.

[0015] The publication "Synthesis and pharmacological evaluation of some
(pyridyl)cyclopropylmethyl amines and their methiodides as nicotinic
receptor ligands" of Guandalini et al. (Il Farmaco 57: 487-496 (2001))
describes the synthesis of a number of pyridyl cyclopropylamine compounds
and their activities at nicotinic acetylcholine receptors.

[0017] Citation of any reference in this section of the application is not
to be construed as an admission that such reference is prior art to the
present application.

SUMMARY OF THE INVENTION

[0018] In one aspect, the invention provides new compounds that exhibit
affinity for a nicotinic acetylcholine receptor.

[0019] In certain embodiments of the invention, such new compounds
desensitize the nicotinic acetylcholine receptor.

[0020] In certain embodiments of the invention, such new compounds
activate or partially activate a nicotinic acetylcholine receptor.

[0021] In certain embodiments of the invention, such new compounds exhibit
higher affinity for a nicotinic acetylcholine receptor of the
α4β2 subtype than for other nicotinic acetylcholine receptor
subtypes.

[0022] Certain new compounds of the invention can be used to treat an
animal suffering a condition, which includes, but is not limited to, a
neurological or psychiatric condition.

[0023] In certain embodiments of the invention, such new compounds can be
used to treat a neurogenerative disorder, such as Alzheimer's disease or
Parkinson's disease.

[0024] In certain embodiments of the invention, such new compounds can be
used to treat age-related or disease-related cognitive impairment.

[0025] Certain new compounds of the invention can be used to treat an
animal suffering from dyskinesias.

[0026] In certain embodiments of the invention, such new compounds can be
used to treat an animal suffering from attention-deficit hyperactivity
disorder.

[0027] Certain new compounds of the invention can be used to treat an
animal suffering from Tourette's syndrome.

[0028] In certain embodiments of the invention, such new compounds can be
used to treat an animal suffering from depression.

[0029] In certain embodiments of the invention, such new compounds can be
used to treat an animal suffering from schizophrenia.

[0030] Certain new compounds of the invention can be used to treat an
animal suffering from nicotine addiction.

[0031] In certain embodiments of the invention, such new compounds can be
used to treat an animal suffering from pain.

[0032] In certain embodiments of the invention, the compounds of the
invention can be used to treat an animal suffering from anxiety.

[0033] Certain new compounds of the invention can be used to treat an
animal suffering from a mood disorder.

[0034] In certain embodiments of the invention, the compounds of the
invention can be used to treat an animal suffering from methamphetamine
addiction.

[0035] In a further aspect, the invention provides methods of treating or
preventing a condition in an animal by administering one or more of the
new compounds ("pyridinyl nicotinic acetylcholine receptor ligands") of
the invention to an animal in need of such treatment. In certain
embodiments, such new pyridinyl nicotinic acetylcholine receptor ligands
effectively treat a neurological condition or a psychiatric condition in
the animal, while producing fewer or reduced side effects compared to
previously available compounds.

[0036] In yet another aspect, the invention provides methods of treating
nicotine dependence by administering one or more pyridinyl nicotinic
acetylcholine receptor ligands of the invention. In certain embodiments,
such new pyridinyl nicotinic acetylcholine receptor ligands effectively
treat nicotine addiction while producing fewer or reduced side effects
compared to previously available medications for treating nicotine
addiction.

[0037] In another aspect, the invention provides methods of treating
depression by administering one or more pyridinyl nicotinic acetylcholine
receptor ligands of the invention. In certain embodiments, such new
pyridinyl nicotinic acetylcholine receptor ligands effectively treat
depression while producing fewer or reduced side effects compared to
previously available antidepressants.

[0038] Another aspect of the invention is to provide novel intermediates
for the synthesis of such new pyridinyl nicotinic acetylcholine receptor
ligands.

[0043] Y is a bond, or --(CH2)q--, optionally substituted with
one or two groups independently selected from methyl, ethyl, propyl,
isopropyl, and cyclopropyl;

[0044] Z is C3-C6 cycloalkyl or a C4-C6
partially-unsaturated carbocycle, and wherein Z is optionally substituted
with one or two C1-C3 alkyl groups;

[0045] R5 is C1-C6 straight chain alkyl; C3-C6
branched chain alkyl; C1-C6 hydroxyalkyl; alkoxyalkyl in which
the alkoxy and alkyl portions each independently contain from 1 to 6
carbon atoms; C1-C6 fluoroalkyl; arylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms; arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms; aryl; biaryl; heteroarylalkyl
in which the alkyl portion contains from 1 to 6 carbon atoms;
heteroarylalkoxy in which the alkoxy portion contains from 1 to 6 carbon
atoms; --(CH2)1-6--O--(CH2)0-6-aryl;
--(CH2)1-6--O--(CH2)0-6-heteroaryl;
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl;
heteroaryl; or a four- to six-membered saturated heterocycle, with the
proviso that R5 is not arylalkoxy or heteroarylalkoxy when Z is
C3-cycloalkyl;

[0050] Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl; C3-C6 branched chain
alkyl; C3-C6 cycloalkyl; aryl; arylalkyl in which the alkyl
portion contains 1 to 6 carbon atoms; --(CO)Rvii; --(CO)ORvii;
--SO2Rvii; or Rv and Rvi form a four- to six-membered
saturated heterocyclic ring having a single nitrogen atom; wherein if one
of Rv and Rvi is --(CO)Rvii or --SO2Rvii, the
other is not --(CO)Rvii or --SO2Rvii;

[0051] Rvii is C1-C6 straight chain alkyl which is
optionally substituted with one or two hydroxyl groups; C3-C6
branched chain alkyl which is optionally substituted with one or two
hydroxyl groups; C3-C6 cycloalkyl, wherein when the cycloalkyl
group contains more than 3 carbon atoms, it is optionally substituted
with one or two hydroxyl groups; aryl which is optionally substituted
with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl group and
one fluorine atom, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl, and wherein if the
C1-C6 straight chain alkyl group, the C3-C6 branched
chain alkyl group or the C3-C6 cycloalkyl group is substituted,
then no more than one heteroatom selected from the oxygen atom in the
hydroxyl group and the sulfur atom in --SO2Rvii is bound to any
single carbon atom; arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; heteroaryl; or heteroarylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms; or

[0052] when Rv is not H and Rvi is either --(CO)Rvii or
--SO2Rvii, Rv and Rvii can be taken together to form
a 4- to 7-membered ring;

[0053] Rviii is hydrogen, C1-C6 straight chain alkyl
optionally substituted with one or two hydroxyl groups or C1-C6
alkoxy groups, wherein if the C1-C6 straight chain alkyl group
is substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group, the oxygen atom in the alkoxy group and the
sulfur atom in --(CH2)rSRviii is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, or one hydroxyl group and one fluorine atom;
heteroaryl that is optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, or one hydroxyl group and one fluorine atom, wherein the
number of substituents does not exceed the number of available C--H and
N--H bonds; or

[0054] Rviii is C(O)Rx;

[0055] Rix is C1-C6 straight chain alkyl optionally
substituted with one or two hydroxyl groups or C1-C6 alkoxy
groups, wherein if the C1-C6 straight chain alkyl group is
substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group, the oxygen atom in the alkoxy group and the
sulfur atom in --(CH2)rSO2Rix is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl; heteroaryl that is optionally substituted
with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl group and
one fluorine atom, or C1-C6 hydroxyalkyl, wherein the number of
substituents does not exceed the number of available C--H and N--H bonds;
or arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms
and the aryl portion is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl;

[0056] Rx is C1-C6 straight chain alkyl optionally
substituted with one or two hydroxyl groups or C1-C6 alkoxy
groups, wherein if the C1-C6 alkyl group is substituted, then
no more than one heteroatom selected from the oxygen atom in the hydroxyl
group and the oxygen atom in the alkoxy group is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, or one hydroxyl group and one fluorine atom;
arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms
and in which the aryl portion is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; C1-C6 monoalkylamino;
or C1-C6 dialkylamino;

[0057] wherein if R5 contains at least one saturated carbon atom and
said R5 is substituted with two substituents independently selected
from C1-C6 alkoxy, alkoxyalkoxy in which the alkoxy portions
each independently contain from 1 to 6 carbon atoms, F, --OH, --NH2,
C1-C6 monoalkylamino, C1-C6 dialkylamino, and
C1-C6 alkylthio, then said two substituents are not bound to
the same saturated carbon atom;

[0058] m is an integer ranging from 1 to 3;

[0059] n is an integer ranging from 1 to 2;

[0060] p is an integer ranging from 0 to 2;

[0061] wherein when n is 2 or p is 2, the carbon atom linked to the oxygen
atom can be substituted with a C1-C6 straight chain alkyl group
or a C3-C6 branched chain alkyl group;

[0062] q is an integer ranging from 1 to 5;

[0063] r is an integer ranging from 0 to 5;

[0064] and pharmaceutically acceptable derivatives thereof.

[0065] In another embodiment, the invention encompasses compounds of
formula I, wherein all variables have the same meanings as set forth
above for the compounds of formula I, and with the proviso that when m is
2 and Y is a bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
wherein Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl; --(CH2)rSRviii when
Rviii is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;
--(CH2)rSO2Rix, --(CH2)rSORix or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, C3-C6
cycloalkyl or phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; and

[0066] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0067] The invention encompasses compounds of formula II:

##STR00002##

[0068] wherein

[0069] Z' is a four- to six-membered saturated heterocycle; a five- or
six-membered partially-unsaturated heterocycle; or a saturated azabicycle
having 4 to 8 carbon atoms; and wherein Z' is linked to Y through a
carbon atom or a nitrogen atom in the Z' ring, and all other variables
have the same meanings as set forth above for the compounds of the
formula I, except R5 may be hydrogen when Z' is a saturated
azabicycle having 4 to 8 carbon atoms, and pharmaceutically acceptable
derivatives thereof.

[0070] In another embodiment, the invention encompasses compounds of
formula II, wherein all variables have the same meanings as set forth
above, except R5 may be hydrogen when Z' is a 5- or 6-membered
partially unsaturated heterocycle or saturated azabicycle having 4 to 8
carbon atoms, or R5 may be hydrogen when m is 1 and Z' is a four- to
six-membered saturated heterocycle and with the proviso that when Z' is a
4- to 6-membered saturated heterocycle or a 5 to 6-membered partially
unsaturated heterocycle, m is 2 and Y is a bond, R5 is not
C1-C6 straight chain alkyl; C3-C6 branched chain
alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi when one of Rv and
Rvi is hydrogen, and the other of Rv and Rvi is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl or when both Rv and Rvi are
independently C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl.

[0073] wherein Ri is a C1-C6 straight chain alkyl group, a
C3-C6 branched chain alkyl group or a C3-C6
cycloalkyl group, and all other variables have the same meanings as set
forth above for the compounds of the formula I, except R5 may be
hydrogen when Z is any one of the defined Z substituents, and
pharmaceutically acceptable derivatives thereof.

[0076] wherein Ri is a C1-C6 straight chain alkyl group, a
C3-C6 branched chain alkyl group or a C3-C6
cycloalkyl group, and all other variables have the same meanings as set
forth above for the compounds of the formula II, except R5 may be
hydrogen when Z' is any one of the defined Z' substituents, and
pharmaceutically acceptable derivatives thereof.

[0081] Y is a bond, or --(CH2)q--, optionally substituted with
one or two groups independently selected from methyl, ethyl, propyl,
isopropyl, and cyclopropyl;

[0082] Z'' is an aryl group; or a partially saturated C9-C16
carbocyclic group having a least one aromatic ring;

[0083] R5 is C1-C6 hydroxyalkyl; alkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms, provided that when Z'' is an aryl group the alkoxyalkyl is
substituted with one or two substituents which are members of the
optional R5 substituents described in formula I, other than a
substituent which is straight or branched chain alkyl; or R5 is
arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms;
arylalkoxy in which the alkoxy portion contains from 1 to 6 carbon atoms;
aryl; biaryl; heteroarylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; heteroarylalkoxy in which the alkoxy portion contains
from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl;
--(CH2)1-6--O--(CH2)0-6-heteroaryl;
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl;
heteroaryl; or a four- to six-membered saturated heterocycle;

[0084] or R5 may be hydrogen when Z'' is a partially saturated
C9-C16 carbocyclic group having at least one aromatic ring;

[0088] Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl; C3-C6 cycloalkyl; aryl; arylalkyl in which the alkyl
portion contains 1 to 6 carbon atoms; --(CO)Rvii; --(CO)ORvii;
--SO2Rvii, or Rv and Rvi form a four- to six-membered
saturated heterocyclic ring having a single nitrogen atom; wherein if one
of Rv and Rvi is --(CO)Rvii or --SO2Rvii, the
other is not --(CO)Rvii or --SO2Rvii;

[0089] Rvii is C1-C6 straight chain alkyl which is
optionally substituted with one or two hydroxyl groups; C3-C6
branched chain alkyl which is optionally substituted with one or two
hydroxyl groups; C3-C6 cycloalkyl, wherein when the cycloalkyl
group contains more than 3 carbon atoms, it is optionally substituted
with one or two hydroxyl groups; aryl which is optionally substituted
with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl group and
one fluorine atom, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl, and wherein if the
C1-C6 straight chain alkyl group, the C3-C6 branched
chain alkyl group or the C3-C6 cycloalkyl group is substituted,
then no more than one heteroatom selected from the oxygen atom in the
hydroxyl group and the sulfur atom in --SO2Rvii is bound to any
single carbon atom; arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; heteroaryl; or heteroarylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms; or

[0090] when Rv is not H and Rvi is either --(CO)Rvii or
--SO2Rvii, Rv and Rvii can be taken together to form
a 4- to 7-membered ring;

[0091] Rviii is hydrogen, C1-C6 straight chain alkyl
optionally substituted with one or two hydroxyl groups or C1-C6
alkoxy groups, wherein if the C1-C6 straight chain alkyl group
is substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group, the oxygen atom in the alkoxy group and the
sulfur atom in --(CH2)rSRviii is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, or one hydroxyl group and one fluorine atom;
heteroaryl that is optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, or one hydroxyl group and one fluorine atom, wherein the
number of substituents does not exceed the number of available C--H and
N--H bonds; or

[0092] Rviii is --C(O)Rx;

[0093] Rix is C1-C6 straight chain alkyl optionally
substituted with one or two hydroxyl groups or C1-C6 alkoxy
groups, wherein if the C1-C6 straight chain alkyl group is
substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group, the oxygen atom in the alkoxy group and the
sulfur atom in --(CH2)rSO2Rix is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl; heteroaryl that is optionally substituted
with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl group and
one fluorine atom, or C1-C6 hydroxyalkyl, wherein the number of
substituents does not exceed the number of available C--H and N--H bonds;
or arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms
and the aryl portion is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl;

[0094] Rx is C1-C6 straight chain alkyl optionally
substituted with one or two hydroxyl groups or C1-C6 alkoxy
groups, wherein if the C1-C6 alkyl group is substituted, then
no more than one heteroatom selected from the oxygen atom in the hydroxyl
group and the oxygen atom in the alkoxy group is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, or one hydroxyl group and one fluorine atom;
arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms
and in which the aryl portion is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; C1-C6 monoalkylamino;
or C1-C6 dialkylamino;

[0095] wherein if R5 contains at least one saturated carbon atom and
said R5 is substituted with two substituents selected from
C1-C6 alkoxy, alkoxyalkoxy in which the alkoxy portions each
independently contain from 1 to 6 carbon atoms, F, --OH, --NH2,
C1-C6 monoalkylamino, C1-C6 dialkylamino, and
C1-C6 alkylthio, said two substituents are not bound to the
same saturated carbon atom;

[0096] m is an integer ranging from 1 to 3;

[0097] n is an integer ranging from 1 to 2;

[0098] p is an integer ranging from 0 to 2;

[0099] wherein when n is 2 or p is 2, the carbon atom linked to the oxygen
atom can be substituted with a C1-C6 straight chain alkyl group
or a C3-C6 branched chain alkyl group;

[0100] q is an integer ranging from 1 to 5;

[0101] r is an integer ranging from 0 to 5; and

[0102] pharmaceutically acceptable derivatives thereof.

[0103] In another embodiment, the invention encompasses compounds of
formula V, wherein all variables have the same meanings as set forth
above for the compounds of formula V, and with the proviso that when Z''
is an aryl group, m is 2 and Y is a bond, R5 is not phenylalkyl in
which the alkyl portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl; and with the proviso
that when Z'' is an aryl group, m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when both Rv and Rvi are
hydrogen, or when one of Rv and Rvi is hydrogen and the other
of Rv and Rvi is C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0107] Y is a bond, or --(CH2)q--, optionally substituted with
one or two groups independently selected from methyl, ethyl, propyl,
isopropyl, and cyclopropyl;

[0108] Z''' is a heteroaryl group or a C8-C9 partially saturated
bicyclic heteroaryl group;

[0109] R5 is C1-C6 hydroxyalkyl; alkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms, provided that when Z''' is a heteroaryl group the alkoxyalkyl is
substituted with one or two substituents which are members of the
optional R5 substituents described in formula I, other than a
substituent which is straight or branched chain alkyl; or R5 is
arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms;
arylalkoxy in which the alkoxy portion contains from 1 to 6 carbon atoms;
aryl; biaryl; heteroarylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; heteroarylalkoxy in which the alkoxy portion contains
from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl;
--(CH2)1-6--O--(CH2)0-6-heteroaryl;
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl;
heteroaryl; or a four- to six-membered saturated heterocycle;

[0110] or R5 may be hydrogen when Z''' is a C8-C9 partially
saturated bicyclic heteroaryl group;

[0114] Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl; C3-C6 cycloalkyl; aryl; arylalkyl in which the alkyl
portion contains 1 to 6 carbon atoms; --(CO)Rvii; --(CO)ORvii;
--SO2Rvii, or Rv and Rvi form a four- or six-membered
saturated heterocyclic ring having a single nitrogen atom; wherein if one
of Rv and Rvi is --(CO)Rvii or --SO2Rvii, the
other is not --(CO)Rvii or --SO2Rvii;

[0115] Rvii is C1-C6 straight chain alkyl which is
optionally substituted with one or two hydroxyl groups; C3-C6
branched chain alkyl which is optionally substituted with one or two
hydroxyl groups; C3-C6 cycloalkyl, wherein when the cycloalkyl
group contains more than 3 carbon atoms, it is optionally substituted
with one or two hydroxyl groups; aryl which is optionally substituted
with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl group and
one fluorine atom, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl, and wherein if the
C1-C6 straight chain alkyl group, the C3-C6 branched
chain alkyl group or the C3-C6 cycloalkyl group is substituted,
then no more than one heteroatom selected from the oxygen atom in the
hydroxyl group and the sulfur atom in --SO2Rvii is bound to any
single carbon atom; arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; heteroaryl; or heteroarylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms; or

[0116] when Rv is not H and Rvi is either --(CO)Rvii or
--SO2Rvii, Rv and Rvii can be taken together to form
a 4- to 7-membered ring;

[0117] Rviii is hydrogen, C1-C6 straight chain alkyl
optionally substituted with one or two hydroxyl groups or C1-C6
alkoxy groups, wherein if the C1-C6 straight chain alkyl group
is substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group, the oxygen atom in the alkoxy group and the
sulfur atom in --(CH2)rSRviii is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, or one hydroxyl group and one fluorine atom;
heteroaryl that is optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, or one hydroxyl group and one fluorine atom, wherein the
number of substituents does not exceed the number of available C--H and
N--H bonds; or

[0118] Rviii is --C(O)Rx;

[0119] Rix is C1-C6 straight chain alkyl optionally
substituted with one or two hydroxyl groups or C1-C6 alkoxy
groups, wherein if the C1-C6 straight chain alkyl group is
substituted, then no more than one heteroatom selected from the oxygen
atom in the hydroxyl group, the oxygen atom in the alkoxy group and the
sulfur atom in --(CH2)rSO2Rix is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl; heteroaryl that is optionally substituted
with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl group and
one fluorine atom, or C1-C6 hydroxyalkyl, wherein the number of
substituents does not exceed the number of available C--H and N--H bonds;
or arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms
and the aryl portion is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl;

[0120] Rx is C1-C6 straight chain alkyl optionally
substituted with one or two hydroxyl groups or C1-C6 alkoxy
groups, wherein if the C1-C6 alkyl group is substituted, then
no more than one heteroatom selected from the oxygen atom in the hydroxyl
group and the oxygen atom in the alkoxy group is bound to any single
carbon atom; C3-C6 branched chain alkyl; C3-C6
cycloalkyl; aryl that is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, or one hydroxyl group and one fluorine atom;
arylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms
and in which the aryl portion is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom; heteroaryl that is optionally substituted with 1 or 2
fluorine atoms, one hydroxyl group, or one hydroxyl group and one
fluorine atom, wherein the number of substituents does not exceed the
number of available C--H and N--H bonds; C1-C6 monoalkylamino;
or C1-C6 dialkylamino;

[0121] wherein if R5 contains at least one saturated carbon atom and
said R5 is substituted with two substituents selected from
C1-C6 alkoxy, alkoxyalkoxy in which the alkoxy portions each
independently contain from 1 to 6 carbon atoms, F, --OH, --NH2,
C1-C6 monoalkylamino, C1-C6 dialkylamino, and
C1-C6 alkylthio, said two substituents are not bound to the
same saturated carbon atom;

[0122] wherein the heteroatoms of Z''' and R5 are not directly
connected to each other through a bond, or separated by a single
saturated carbon atom, or connected to each other through a C═C
double bond; with the exception that if R5 is SO2Rix and
Z''' is a nitrogen containing heteroaryl group, the sulfur atom in said
R5 can be directly attached to a nitrogen atom in Z''';

[0123] m is an integer ranging from 1 to 3;

[0124] n is an integer ranging from 1 to 2;

[0125] p is an integer ranging from 0 to 2;

[0126] wherein when n is 2 or p is 2, the carbon atom linked to the oxygen
atom can be substituted with a C1-C6 straight chain alkyl group
or a C3-C6 branched chain alkyl group;

[0127] q is an integer ranging from 1 to 5;

[0128] r is an integer ranging from 0 to 5; and

[0129] pharmaceutically acceptable derivatives thereof.

[0130] In another embodiment, the invention encompasses compounds of
formula VI, wherein all variables have the same meanings as set forth
above for the compounds of formula VI, and with the proviso that when
Z''' is a heteroaryl group, m is 2 and Y is a bond, R5 is not
phenylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;

[0131] with the proviso that when Z''' is pyridine, m is 2, and Y is a
bond, R5 is not --CH2OH; and

[0132] with the proviso that when Z''' is a heteroaryl group, m is 1 or 3
and Y is a bond, R5 is not --(CH2)rNRvRvi when
both Rv and Rvi are hydrogen, or when one of Rv and
Rvi is hydrogen and the other of Rv and Rvi is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl.

[0135] wherein Ri is hydrogen, C1-C6 straight chain alkyl
group, a C3-C6 branched chain alkyl group, or a C3-C6
cycloalkyl group, and all other variables have the same meanings as set
forth above for the compounds of the formula V, except that R5 may
also be hydrogen, and pharmaceutically acceptable derivatives thereof.

[0136] The invention encompasses compounds of formula VIII:

##STR00011##

[0137] wherein Riv is hydrogen, a C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
or an acyl group having the formula:

##STR00012##

[0138] wherein Ri is a C1-C6 straight chain alkyl group, a
C3-C6 branched chain alkyl group, or a C3-C6
cycloalkyl group, and all other variables have the same meanings as set
forth above for the compounds of the formula VI, except that R5 may
also be hydrogen, and pharmaceutically acceptable derivatives thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0139] As used in connection with the pyridinyl nicotinic acetylcholine
receptor ligands herein, the terms used herein having the following
meanings:

[0140] The term "agonist" refers to a compound that binds to a particular
receptor and triggers a response in the cell. It mimics the activity of
the endogenous ligand (e.g., acetylcholine) that binds to the same
receptor.

[0141] The term "antagonist" refers to a compound that binds to a receptor
site but does not cause any physiological changes unless another receptor
ligand is present.

[0142] The term "partial agonist" refers to a compound that binds to a
receptor site but does not produce the maximal effect, regardless of its
concentration.

[0143] The term "competitive antagonist" refers to a compound that binds
to a receptor site, the effect of which can be overcome by increasing the
concentration of the agonist.

[0144] The term "ligand" refers to a compound that binds at a receptor
site.

[0147] "C1-C6 fluoroalkyl" means a straight chain hydrocarbon
radical having from 1 to 6 carbon atoms, in which between 1 and 4
hydrogen atoms are substituted by a fluorine atom.

[0148] "C1-C6 hydroxyalkyl" means a straight chain hydrocarbon
radical having from 1 to 6 carbon atoms, in which 1 hydrogen atom bound
to a carbon atom is substituted by one hydroxyl group, or 2 hydrogen
atoms that are bound to different carbon atoms are each substituted by
one hydroxyl group.

[0155] "A five- or six-membered partially-unsaturated heterocycle" means
non-aromatic 5- or 6-membered ring structures containing 1 or 2
heteroatoms, which are preferably nitrogen, oxygen or sulfur, and
containing one carbon-carbon or carbon-nitrogen double bond.
Partially-unsaturated heterocycles can also be polycycles, which means
that they are optionally fused to a cycloalkyl, a partially-unsaturated
carbocycle, an aryl group, a partially-unsaturated heterocycle or a
heteroaryl group. Representative partially-unsaturated heterocycles
include 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,5-dihydrothiophene,
4,5-dihydrooxazole, 4,5-dihydrothiazole, 4,5-dihydro-1H-imidazole,
4,5-dihydro-1H-1,2,3-triazole, 1,2,5,6-tetrahydropyridine,
1,4,5,6-tetrahydropyrimidine, 2,5,6,7-tetrahydro-1H-azepine,
1,3,4,5,6,7-hexahydroisobenzofuran, and 2H-chromene.

[0156] "Partially saturated C9-C16 carbocyclic group having at
least one aromatic ring" means a bi- or tri-carbocyclic ring system
having from 9 to 16 carbon atoms and wherein the ring closest to the
pyridine group in Formula V is an aromatic ring and one ring is a five-
or six-membered alicyclic ring which is saturated except for the carbon
atoms shared with the aromatic ring.

[0157] "C8-C9 partially saturated bicyclic heteroaryl" means a
single five- or six-membered heterocyclic ring containing either a single
nitrogen or oxygen atom wherein the heterocyclic ring is fully saturated
except those carbon atoms shared with a fused benzene ring and wherein
either the benzene ring or the heterocyclic ring is linked to Y. Examples
include 2,3-dihydro-1H-isoindole, 1,2,3,4-tetrahydroquinoline,
2,3-dihydro-1H-indole, 1,2,3,4-tetrahydroisoquinoline,
2,3-dihydrobenzofuran, chroman and isochroman.

[0160] "Biaryl" means a group containing two aromatic rings that contain
only carbon atoms, and in which the two aromatic rings are connected by a
single bond. Representative biaryl groups include biphenyl.

[0162] The phrases "treatment of," "treating", and the like include the
amelioration or cessation of a condition or a symptom thereof. In one
embodiment, treating includes inhibiting, for example, decreasing the
overall frequency of episodes of a condition or a symptom thereof.

[0163] The phrases "prevention of," "preventing", and the like include the
avoidance of the onset of a condition or a symptom thereof.

[0165] The phrase "pharmaceutically acceptable derivative," as used
herein, includes any pharmaceutically acceptable salt, prodrug,
radiolabeled form, stereoisomer, enantiomer, diastereomer, other
stereoisomeric form, racemic mixture, geometric isomer, tautomer, solvate
(e.g., hydrate, or addition compounds that contain acid in excess of the
number of their basic nitrogen atoms due to hydrogen bonding), amorphous
solid form and crystalline solid form, e.g., of a pyridinyl nicotinic
acetylcholine receptor ligand of the invention. In one embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable
salt, radiolabeled form, stereoisomer, enantiomer, diastereomer, other
stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,
e.g., of a pyridinyl nicotinic acetylcholine receptor ligand of the
invention. In another embodiment, the pharmaceutically acceptable
derivative is a pharmaceutically acceptable salt, e.g., of a pyridinyl
nicotinic acetylcholine receptor ligand of the invention.

[0166] The phrase "pharmaceutically acceptable salt," as used herein, is
any pharmaceutically acceptable salt that can be prepared from a
pyridinyl nicotinic acetylcholine receptor ligand including a salt formed
from an acid and a basic functional group, such as a nitrogen group, of a
pyridinyl nicotinic acetylcholine receptor ligand. Illustrative salts
include, but are not limited, to sulfate, citrate, acetate,
trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,
phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid
citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, malate, maleate, gentisinate, fumarate, gluconate,
glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoroacetate,
and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
One skilled in the art will recognize that acid addition salts of a
pyridinyl nicotinic acetylcholine receptor ligand can be prepared by
reaction of the compounds with the appropriate acid via a variety of
known methods, or by reacting another salt of the compound with an anion
exchanger containing the anion of the desired acid.

[0167] The invention disclosed herein is also meant to encompass all
prodrugs of the pyridinyl nicotinic acetylcholine receptor ligands.
"Prodrugs" are known in the art and, while not necessarily possessing any
pharmaceutical activity as such, are considered to be any covalently
bonded carrier(s) that releases the active parent drug in vivo. In
general, such prodrugs will be a functional derivative of a pyridinyl
nicotinic acetylcholine receptor ligand of formulas I-VIII which is
readily convertible in vivo, e.g., by being metabolized, into the
required pyridinyl nicotinic acetylcholine receptor ligand of formulas
I-VIII. Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described in, for example, Design of
Prodrugs, H. Bundgaard ed., Elsevier (1985); "Drug and Enzyme Targeting,
Part A," K. Widder et al. eds., Vol. 112 in Methods in Enzymology,
Academic Press (1985); Bundgaard, "Design and Application of Prodrugs,"
Chapter 5 (pp. 113-191) in A Textbook of Drug Design and Development, P.
Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers
(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);
Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,
Chem. Pharm. Bull. 32:692 (1984).

[0168] In addition, one or more hydrogen, carbon or other atoms of a
pyridinyl nicotinic acetylcholine receptor ligand can be replaced by an
isotope of the hydrogen, carbon or other atoms. Such a "labeled" or
"radiolabeled" form of a pyridinyl nicotinic acetylcholine receptor
ligand, each of which is encompassed by the invention, is useful as a
research tool in metabolism, pharmacokinetic studies, and in binding
assays, and/or as a diagnostic tool. Examples of isotopes that can be
incorporated into a pyridinyl nicotinic acetylcholine receptor ligand of
the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H,
11C, 13C, 14C, 15N, 18O, 17O, 35S,
18F, 32P, and 36Cl, respectively. Labeled compounds of the
invention can be prepared by methods known in the art. For example,
tritiated compounds of Formula (I) can be prepared by introducing tritium
into the particular compound of Formula (I), for example, by catalytic
dehalogenation with tritium. This method can include reacting a suitably
halogen-substituted precursor of a compound of Formula (I) with tritium
gas in the presence of a suitable catalyst, for example, Pd/C, in the
presence or absence of a base. Other suitable methods for preparing
tritiated compounds can be found in Filer, Isotopes in the Physical and
Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6
(1987). 14C-labeled compounds can be prepared by employing starting
materials having a 14C carbon.

[0169] A pyridinyl nicotinic acetylcholine receptor ligand can contain one
or more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The invention is also
meant to encompass all such possible forms as well as their racemic and
resolved forms or any mixture thereof. All "tautomers," e.g.,
amide-imidic acid, lactam-lactim, and enamine-imine tautomers, are
intended to be encompassed by the invention as well.

[0170] As used herein, the terms "stereoisomer," "stereoisomeric form",
and the like are general terms for all isomers of individual molecules
that differ only in the orientation of their atoms in space. It includes
enantiomers and isomers of compounds with more than one chiral center
that are not mirror images of one another ("diastereomers").

[0171] The term "chiral center" refers to a carbon atom to which four
different groups are attached.

[0172] The term "enantiomer" or "enantiomeric" refers to a molecule that
is nonsuperimposable on its mirror image and hence optically active where
one enantiomer rotates the plane of polarized light in one direction and
its minor image rotates the plane of polarized light in the opposite
direction. In rare cases, and then typically dependent on the choice of
solvent, pH, and concentration, the extent to which an enantiomer rotates
the plane of polarized light may be too small to be measured.

[0173] The term "racemic" refers to a mixture of equal parts of
enantiomers which by mutual cancellation of each other's contribution to
the mixture's optical rotation is optically inactive.

[0174] The term "resolution" refers to the separation or concentration or
depletion of one of the two enantiomeric forms of a molecule.

[0175] Optical isomers of a pyridinyl nicotinic acetylcholine receptor
ligand can be obtained by known techniques such as chiral chromatography
or formation of diastereomeric salts from an optically active acid or
base.

[0176] The nicotinic acetylcholine receptor ligands of the invention may
exist in solid form, which may be an amorphous form or crystalline form.
The present invention encompasses all such amorphous and crystalline
solid forms of the compounds of formulas I-VIII. By "crystalline form" is
meant that the molecules are in a crystal lattice--a regular,
three-dimensional arrangement of points in space at which the molecules
are located. The unit cell is the smallest building block of a crystal
whose geometric arrangement defines the characteristic symmetry of a
crystal and whose repetition in three dimensions produces a crystal
lattice. Small molecules often crystallize in more than one crystal
lattice, which are known as polymorphs. Solvent molecules may also be
incorporated into a crystal lattice and may be ordered (e.g., occurring
at the same place in every unit cell) or disordered (e.g., filling a
channel in the crystal). A crystal with solvent incorporated into the
lattice is called a solvate. If the solvent is water, then the crystal
form is a hydrate. Hydrates and solvates are sometimes known as
pseudopolymorphs. The crystalline form obtained for a particular
substance may depend on any number of factors, including temperature,
solvent, time for crystallization, and the addition to the solution of
the substance of seeding crystals of one of its polymorphs or
pseudopolymorphs.

[0178] The phrase "effective amount," when used in connection with a
second therapeutic agent means an amount for providing the therapeutic
effect of the second therapeutic agent.

[0179] The terms "modulate," "modulating", and the like as used herein
with respect to nicotinic acetylcholine receptors mean the mediation of a
pharmacologic response (e.g., antidepressant) in an animal from (i)
inhibiting or activating the receptor, or (ii) directly or indirectly
affecting the normal regulation of the receptor activity. Compounds that
modulate the receptor activity include agonists, antagonists, mixed
agonists/antagonists and compounds which directly or indirectly affect
regulation of the receptor activity.

[0180] The term "nicotinic acetylcholine receptor" and the abbreviation
"nAChR" refer to a functional ligand-gated ion channel that is a homo- or
hetero-pentamer of protein subunits designated as α1-α10,
β1-β4, δ, γ and ε, the opening of which is
triggered by acetylcholine or nicotine. nAChR subtypes are identified by
their known subunit compositions, which includes an asterisk ("*") when
other unknown subunits are or could be present in the pentamer, e.g., the
α3* nAChR subtype found in the brain is composed of at least one
α3 subunit and other subunits that have not yet been identified,
whereas the α4β2 nAChR subtype found in the vertebrate central
nervous system is composed only of α4 and β2 subunits.

[0181] The term "HPLC" means high performance liquid chromatography.

[0182] The term "TLC" means thin layer chromatography.

[0183] The term "CC" means column chromatography.

[0184] The term "CDCl3" means deuterated chloroform.

[0185] The term "PPh3" means triphenylphosphine.

[0186] The term "THF" means tetrahydrofuran.

[0187] The term "SiO2" means chromatographic grade silica gel.

[0188] The term "EtOAc" means ethyl acetate.

[0189] The term "DME" means 1,2-dimethoxyethane.

[0190] The term "DMF" means N,N-dimethylformamide.

[0191] The term "MeOH" means methanol, i.e., methyl alcohol.

[0192] The term "EtOH" means ethanol, i.e., ethyl alcohol.

[0193] The term "NH4Cl" means ammonium chloride.

[0194] The term "Na2SO4" means sodium sulfate.

[0195] The terms "DCM" and "CH2Cl2" mean dichloromethane, also
referred to as methylene chloride or methylene dichloride.

[0196] The term "Et2Zn" means diethylzinc.

[0197] The term "NaHCO3" means sodium bicarbonate.

[0198] The term "HCl" means hydrogen chloride. If a solvent other than
water is specified, "HCl" specifically means a solution of anhydrous
(gaseous) hydrogen chloride in that solvent.

[0199] The term "Na2SO3" means sodium sulfite.

[0200] The terms "CF3CO2H" and "CF3COOH" mean
trifluoroacetic acid.

[0201] The term "CH3CN" means acetonitrile.

[0202] The term "NaOH" means sodium hydroxide.

[0203] The term "p-TsCl" means para-toluenesulfonyl chloride, also known
as tosyl chloride.

[0224] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula I.

[0225] In another embodiment, the invention encompasses compounds of
formula I, wherein all variables have the same meanings as set forth
above for the compounds of formula I, and with the proviso that when m is
2 and Y is a bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
wherein Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl; --(CH2)rSRviii when
Rviii is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;
--(CH2)rSO2Rix, --(CH2)rSORix or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, C3-C6
cycloalkyl or phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; and

[0226] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0227] In another embodiment, R1 is H.

[0228] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0229] In another embodiment, R1 is C3-C6 branched chain
alkyl.

[0230] In another embodiment, R1 is allyl.

[0231] In another embodiment, R1 is C3-C6 cycloalkyl.

[0232] In another embodiment, R2 is H.

[0233] In another embodiment, R3 is H.

[0234] In another embodiment, R4 is H.

[0235] In another embodiment, R2, R3 and R4 are each H.

[0236] In another embodiment, m is 1.

[0237] In another embodiment, m is 2.

[0238] In another embodiment, m is 3.

[0239] In another embodiment, n is 1.

[0240] In another embodiment, n is 2.

[0241] In another embodiment, p is 0.

[0242] In another embodiment, p is 1.

[0243] In another embodiment, p is 2.

[0244] In another embodiment, n is 1 and p is 0.

[0245] In one embodiment, Y is --CH2-- and Z is C3-C6
cycloalkyl.

[0246] In another embodiment, Y is --CH2-- and Z is a C4-C6
partially unsaturated carbocycle.

[0247] In another embodiment, Y is --CH2CH2-- and Z is
C3-C6 cycloalkyl.

[0248] In another embodiment, Y is --CH2CH2-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0249] In another embodiment, Y is --CH2CH2CH2-- and Z is
C3-C6 cycloalkyl.

[0250] In another embodiment, Y is --CH2CH2CH2-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0251] In another embodiment, Y is --(CH2)4-- and Z is
C3-C6 cycloalkyl.

[0252] In another embodiment, Y is --(CH2)4-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0253] In another embodiment, Y is --(CH2)5-- and Z is
C3-C6 cycloalkyl.

[0254] In another embodiment, Y is --(CH2)5-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0255] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0256] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0257] In another embodiment, m is 1, Y is a bond, Z is C3-C6
cycloalkyl, p is 0, R1, R2, R3, and R4 are each
hydrogen, R5 is alkoxyalkyl, in which the alkoxy and alkyl portions
each independently contain between 1 to 6 carbon atoms, and said
alkoxylalkyl is substituted with either aryloxy; heteroaryloxy; or
C3-C6 cycloalkyloxy.

[0258] In another embodiment, m is 1, Y is a bond, Z is 1,2-disubstituted
cyclopropyl, p is 0, R1, R2, R3, and R4 are each
hydrogen, R5 is alkoxyalkyl, in which the alkoxy and alkyl portions
each independently contain between 1 to 6 carbon atoms, and said
alkoxylalkyl is substituted with either aryloxy; heteroaryloxy; or
C3-C6 cycloalkyloxy.

[0259] In another embodiment, m is 1, Y is a bond and Z is C3-C6
cycloalkyl.

[0260] In another embodiment, m is 1, Y is a bond and Z is a
C4-C6 partially unsaturated carbocycle.

[0261] In another embodiment, m is 3, Y is a bond and Z is C3-C6
cycloalkyl.

[0262] In another embodiment, m is 3, Y is a bond and Z is a
C4-C6 partially unsaturated carbocycle.

[0263] In another embodiment, m is 1 or 3, Y is a bond, Z is
C3-C6 cycloalkyl or a C4-C6 partially unsaturated
carbocycle, and if Z is a six-membered ring, R5 is in the meta
position on said ring with respect to the pyridine ring.

[0264] In another embodiment, m is 1 or 3, Y is a bond, Z is
C3-C6 cycloalkyl or a C4-C6 partially unsaturated
carbocycle, and if Z is a six-membered ring, R5 is in the para
position on said ring with respect to the pyridine ring.

[0265] In another embodiment, m is 1 or 3, Y is a bond, Z is
C3-C6 cycloalkyl or a C4-C6 partially unsaturated,
and if Z is a six-membered ring, R5 is in the ortho position on said
ring with respect to the pyridine ring.

[0266] In one embodiment, Z is a 1,2-disubstituted cyclopropyl group.

[0267] In another embodiment, Z is a 1,2-disubstituted cyclobutyl group.

[0268] In another embodiment, Z is a 1,3-disubstituted cyclobutyl group.

[0269] In another embodiment, Z is a 1,2- or 1,3-disubstituted cyclopentyl
group.

[0270] In another embodiment, Z is a 1,2-, 1,3- or 1,4-disubstituted
cyclohexyl group.

[0271] In another embodiment, R5 is C1-C6 hydroxyalkyl.

[0272] In another embodiment, R5 is alkoxyalkyl with one or two
hydroxyl substituents and in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms.

[0273] In another embodiment, R5 is hydroxyalkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms.

[0274] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0275] In another embodiment, R5 is aryl.

[0276] In another embodiment, R5 is biaryl.

[0277] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0278] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0279] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0280] In another embodiment, R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0281] In another embodiment, R5 is heteroaryl.

[0282] In another embodiment, R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl and the other of
Rv and Rvi is --(CO)Rvii or --SO2Rvii, and r and
Rvii are as described above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula I.

[0283] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, and r, Rv and Rvi are
as described above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula I.

[0284] In another embodiment, R5 is --(CH2)rSRviii,
wherein Rviii is hydrogen or --C(O)Rx, and r and Rx are as
defined above for the pyridinyl nicotinic acetylcholine receptor ligands
of the formula I.

[0285] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r is an integer ranging from
0 to 5 and Rix is as defined above for the compounds of formula I.

[0286] In another embodiment, R5 is --(CH2)rSORix,
wherein r is an integer ranging from 0 to 5 and Rix is as defined
above for the compounds of formula I.

[0287] In another embodiment R5 is --(CH2)rC(O)ORix,
wherein r is an integer ranging from 0 to 5 and Rix is as defined
above for the compounds of formula I.

[0288] In another embodiment, Y is a bond, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is C1-C6 hydroxyalkyl.

[0289] In another embodiment, Y is --CH2--, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2OH.

[0290] In another embodiment, Y is --(CH2)2--, Z is a
1,2-disubstituted cyclopropyl ring and R5 is --(CH2)2OH.

[0291] In another embodiment, m is 1 or 2, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is C1-C6 hydroxyalkyl.

[0292] In another embodiment, m is 1, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --(CH2)4OH.

[0293] In another embodiment, m is 1, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2CH2OH.

[0294] In another embodiment, m is 1, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2OH.

[0295] In another embodiment, m is 1, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is C1-C6 fluoroalkyl.

[0296] In another embodiment, m is 1, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2CH2F.

[0297] In another embodiment, m is 1, Y is a bond, n is 1, p is 0,
R2, R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is --CH2F.

[0298] In another embodiment, Y is a bond, n is 1, p is 0, R2,
R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is
--(CH2)1-6--O--(CH2)0-6-aryl, wherein the aryl is
optionally substituted with 1 or 2 fluorine atoms, one hydroxyl group,
one hydroxyl group and one fluorine atom, Cl or OCF3.

[0299] In another embodiment, Y is a bond, n is 1, p is 0, R2,
R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl, wherein the
heteroaryl is optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, one hydroxyl group and one fluorine atom, Cl or
OCF3.

[0300] In another embodiment, Y is a bond, n is 1, p is 0, R2,
R3 and R4 are each hydrogen, Z is a 1,2-disubstituted
cyclopropyl ring and R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl,
wherein the heteroaryl is optionally substituted with 1 or 2 fluorine
atoms, one hydroxyl group, one hydroxyl group and one fluorine atom, Cl
or OCF3.

[0301] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is
--(CH2)rNRvRvi, wherein r is 1 or 2 and each of
Rv and Rvi is H.

[0302] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is
--(CH2)rNRvRvi, wherein r is 2, and one of Rv
and Rvi is H and the other of Rv and Rvi is
--(CO)Rvii wherein Rvii is C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, aryl that is optionally
substituted with 1 or 2 fluorine atoms, one hydroxyl group, or one
hydroxyl group and one fluorine atom, or R5 is heteroaryl optionally
substituted with 1 or 2 fluorine atoms, one hydroxyl group, or one
hydroxyl group and one fluorine atom, wherein the number of substituents
does not exceed the number of available C--H and N--H bonds.

[0303] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is
--(CH2)rNRvRvi, wherein r is 2, and one of Rv
and Rvi is H and the other of Rv and Rvi is
--SO2Rvii, wherein Rvii is C1-C6 straight chain
alkyl, aryl that is optionally substituted with 1 or 2 fluorine atoms,
one hydroxyl group, or one hydroxyl group and one fluorine atom, or
R5 is heteroaryl optionally substituted with 1 or 2 fluorine atoms,
one hydroxyl group, or one hydroxyl group and one fluorine atom, wherein
the number of substituents does not exceed the number of available C--H
and N--H bonds.

[0304] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring, and R5 is --CH2OCH3,
--CH2CH2OCH3 or --CH2CH2OCH2CF3.

[0305] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is
--(CH2)rSRviii, wherein r is 1 or 2 and Rviii is
--CH3.

[0306] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is
--(CH2)rSRviii, wherein r is 1 or 2 and Rviii is
phenyl.

[0307] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring and R5 is
--(CH2)rSORix, wherein r is 1 or 2 and Rix is
--CH3, C3-C6 branched chain alkyl, aryl that is optionally
substituted with 1 or 2 fluorine atoms, one hydroxyl group, one hydroxyl
group and one fluorine atom, or C1-C6 hydroxyalkyl, or Rix
is arylalkyl optionally substituted with 1 or 2 fluorine atoms, one
hydroxyl group, one hydroxyl group and one fluorine atom, or
C1-C6 hydroxyalkyl, wherein the number of substituents does not
exceed the number of available C--H and N--H bonds.

[0308] In another embodiment, m is 1, Y is a bond, Z is a
1,2-disubstituted cyclopropyl ring, and R5 is
--(CH2)rSO2Rix, wherein r and Rix are as defined
above for the pyridinyl nicotinic acetylcholine receptor ligands of the
formula I.

[0309] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is selected from the
group consisting of C1-C6 hydroxyalkyl, C1-C6
fluoroalkyl, alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms,
--(CH2)1-6--O--(CH2)0-6-heteroaryl, and R5 is
optionally substituted by the optional substituents defined in formula I.

[0310] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is C1-C6
hydroxyalkyl.

[0311] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is alkoxyalkyl in which
the alkoxy and the alkyl portions each independently contain from 1 to 6
carbon atoms and said alkoxyalkyl is optionally substituted by the
optional substituents defined in formula I.

[0312] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is
--CH2CH2OH.

[0313] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is C1-C6
fluoroalkyl.

[0314] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is
--(CH2)1-6--O--(CH2)0-6-aryl which is optionally
substituted by the optional substituents defined in formula I.

[0315] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl which is
optionally substituted by the optional substituents defined in formula I.

[0316] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is
--(CH2)1-6--O--(CH2)0-6-phenyl, wherein the phenyl
group is optionally substituted with substitutents selected from one or
two fluoro atoms, one hydroxyl, one fluoro and one hydroxyl, --CF3,
and --OCF3.

[0317] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl, wherein the
heteroaryl group is optionally substituted with substitutents selected
from one or two fluoro atoms, one hydroxyl, one fluoro and one hydroxyl,
--CF3, and --OCF3.

[0318] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z is
a 1,2-disubstituted cyclopropyl ring, and R5 is
--(CH2)1-6--O--(CH2)0-6-pyridinyl, and wherein the
pyridinyl group is optionally substituted by the optional substituents
defined in formula I.

[0319] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R5 is alkoxyalkyl in which the alkoxy and alkyl portions
each independently contain from 1 to 6 carbon atoms and said alkoxyalkyl
is optionally substituted by the optional substituents defined in formula
I.

[0320] In another embodiment of formula I, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen,
R5 is alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms and said alkoxyalkyl is
substituted with one hydroxyl substituent.

[0321] The present invention encompasses compounds of the formula I-1:

##STR00016##

[0322] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula I.

[0323] In another embodiment, the invention encompasses the compounds of
formula I-1, wherein all variables are as defined above for the compounds
of formula I, and with the proviso that when m is 2 and Y is a bond,
R5 is not C1-C6 straight chain alkyl; C3-C6
branched chain alkyl; alkoxyalkyl in which the alkoxy and alkyl portions
each independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; and

[0324] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0325] In another embodiment, the present invention encompasses the
compounds of formula I-1, and pharmaceutically acceptable derivatives
thereof, wherein each of R1, R2 and R3 is hydrogen, and
all other variables have the same meanings as set forth above for the
compounds of formula I.

[0326] In another embodiment, the present invention encompasses the
compounds of formula I-1, and pharmaceutically acceptable derivatives
thereof, wherein each of R1, R2 and R3 is hydrogen, and
all other variables have the same meanings as set forth above for the
compounds of formula I, and with the proviso that when m is 2 and Y is a
bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
wherein Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl; --(CH2)rSRviii when
Rviii is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;
--(CH2)rSO2Rix, (CH2)rSORix or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, C3-C6
cycloalkyl or phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; and

[0327] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0328] In another embodiment, the present invention encompasses compounds
of formula I-1, and pharmaceutically acceptable derivatives thereof,
wherein n is 1, p is 0, and all other variables have the same meanings as
set forth above for the compounds of formula I.

[0329] In yet another embodiment, the present invention encompasses
compounds of formula I-1, and pharmaceutically acceptable derivatives
thereof, wherein Y is a bond and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0330] In another embodiment, the present invention encompasses compounds
of formula I-1, and pharmaceutically acceptable derivatives thereof,
wherein Y is --CH2-- and all other variables have the same meanings
as set forth above for the compounds of formula I.

[0331] In another embodiment, the present invention encompasses compounds
of formula I-1, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)2-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0332] In another embodiment, the present invention encompasses compounds
of formula I-1, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)3-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0333] In another embodiment, the present invention encompasses compounds
of formula I-1, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)4-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0334] In another embodiment, the present invention encompasses compounds
of formula I-1, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)5-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0335] In another embodiment, the invention encompasses the compounds of
formula I-1, and pharmaceutically acceptable derivatives thereof, wherein
R5 is C1-C6 hydroxyalkyl, and all other variables have the
same meanings as defined above for the compounds of formula I.

[0336] In another embodiment, the invention encompasses the compounds of
formula I-1 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0337] In another embodiment, the invention encompasses the compounds of
formula I-1 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0338] In another embodiment, the invention encompasses the compounds of
formula I-1, and pharmaceutically acceptable derivatives thereof, werein
R5 is --(CH2)rC(O)NRvRvi, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0339] In another embodiment, the invention encompasses the compounds of
formula I-1, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, and all other variables have the
same meanings as set forth above for the compounds of formula I.

[0340] In another embodiment, the invention encompasses the compounds of
formula I-1, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rC(O)ORix, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0341] In another embodiment, the invention encompasses the compounds of
formula I-1, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)1-6--O--(CH2)0-6-aryl, and all
other variables have the same meanings as set forth above for the
compounds of formula I.

[0342] In another embodiment, the invention encompasses the compounds of
formula I-1, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSRviii, wherein Rviii is aryl or
--C(O)Rx, and all other variables have the same meanings as set
forth above for the compounds of formula I.

[0343] In another embodiment, the present invention encompasses compounds
of formula I-2:

##STR00017##

[0344] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the pyridinyl
nicotinic acetylcholine receptor ligands of the formula I.

[0345] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein n is 1, p is 0, and all other variables have the same meanings as
set forth above for the compounds of formula I, with the proviso that
when Y is a bond, R5 is not --(CH2)rNRvRvi when
Rv and Rvi are each independently hydrogen, C1-C6
straight chain alkyl, C3-C6 branched chain alkyl or
C3-C6 cycloalkyl.

[0346] In yet another embodiment, the present invention encompasses
compounds of formula I-2, and pharmaceutically acceptable derivatives
thereof, wherein Y is a bond and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0347] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein Y is --CH2-- and all other variables have the same meanings
as set forth above for the compounds of formula I.

[0348] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)2-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0349] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)3-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0350] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)4-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0351] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)5-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0352] In another embodiment, the present invention encompasses compounds
of formula I-2, and pharmaceutically acceptable derivatives thereof,
wherein R5 is C1-C6 hydroxyalkyl or alkoxyalkyl, in which
the alkoxy and alkyl portions each independently contain between 1 to 6
carbon atoms, and all other variables have the same meanings as set forth
above for the compounds of formula I.

[0353] In another embodiment, the invention encompasses the compounds of
formula I-2 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0354] In another embodiment, the invention encompasses the compounds of
formula I-2 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0355] In another embodiment, the invention encompasses the compounds of
formula I-2, and pharmaceutically acceptable derivatives thereof, werein
R5 is --(CH2)rC(O)NRvRvi, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0356] In another embodiment, the invention encompasses the compounds of
formula I-2, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, and all other variables have the
same meanings as set forth above for the compounds of formula I.

[0357] In another embodiment, the invention encompasses the compounds of
formula I-2, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rC(O)ORix, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0358] In another embodiment, the invention encompasses the compounds of
formula I-2, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)1-6--O--(CH2)0-6-aryl, and all
other variables have the same meanings as set forth above for the
compounds of formula I.

[0359] In another embodiment, the invention encompasses the compounds of
formula I-2, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSRviii, wherein Rviii is aryl or
--C(O)Rx, and all other variables have the same meanings as set
forth above for the compounds of formula I.

[0360] In another embodiment, the present invention encompasses compounds
of formula I-3:

##STR00018##

[0361] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0362] In another embodiment, the invention encompasses the compounds of
formula I-3, wherein R1, R5, Y, n and p have the same meanings
as set forth above for the compounds of formula I, and with the proviso
that when Y is a bond, R5 is not C1-C6 straight chain
alkyl; C3-C6 branched chain alkyl; alkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms; C1-C6 fluoroalkyl; phenylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi wherein Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms.

[0363] In another embodiment, the present invention encompasses compounds
of formula I-3, and pharmaceutically acceptable derivatives thereof,
wherein Y is --CH2-- and all other variables have the same meanings
as set forth above for the compounds of formula I.

[0364] In another embodiment, the present invention encompasses compounds
of formula I-3, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)2-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0365] In another embodiment, the present invention encompasses compounds
of formula I-3, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)3-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0366] In another embodiment, the present invention encompasses compounds
of formula I-3, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)4-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0367] In another embodiment, the present invention encompasses compounds
of formula I-3, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)5-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0368] In another embodiment, the present invention encompasses compounds
of formula I-3, and pharmaceutically acceptable derivatives thereof,
wherein R5 is C1-C6 hydroxyalkyl and all other variables
have the same meanings as set forth above for the compounds of formula I.

[0369] In another embodiment, the invention encompasses the compounds of
formula I-3 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0370] In another embodiment, the invention encompasses the compounds of
formula I-3 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0371] In another embodiment, the invention encompasses the compounds of
formula I-3, and pharmaceutically acceptable derivatives thereof, werein
R5 is --(CH2)rC(O)NRvRvi, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0372] In another embodiment, the invention encompasses the compounds of
formula I-3, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, and all other variables have the
same meanings as set forth above for the compounds of formula I.

[0373] In another embodiment, the invention encompasses the compounds of
formula I-3, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)1-6--O--(CH2)0-6-aryl or
--(CH2)1-6--O--(CH2)0-6-heteroaryl, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0374] In another embodiment, the invention encompasses the compounds of
formula I-1 through I-3 and pharmaceutically acceptable derivatives
thereof, wherein R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl and all other
variables have the same meaning set forth above for the compounds of
formula I.

[0375] In another embodiment, the invention encompasses the compounds of
formula I-3, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSRviii, wherein Rviii is aryl or
--C(O)Rx, and all other variables have the same meanings as set
forth above for the compounds of formula I.

[0376] In another embodiment, the invention encompasses the compounds of
formula I-4:

##STR00019##

[0377] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0378] In another embodiment, the invention encompasses the compounds of
formula I-4, wherein all variables have the same meanings as set forth
above for the compounds of formula I, and with the proviso that when m is
2 and Y is a bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
wherein Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl; --(CH2)rSRviii when
Rviii is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;
--(CH2)rSO2Rix, --(CH2)rSORix or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, C3-C6
cycloalkyl or phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; and

[0379] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0380] In one embodiment, R5 is in the ortho position on the
cyclohexyl ring with respect to Y.

[0381] In another embodiment, R5 is in the meta position on the
cyclohexyl ring with respect to Y.

[0382] In another emobiment, R5 is in the para position on the
cyclohexyl ring with respect to Y.

[0383] In yet another embodiment, the present invention encompasses
compounds of formula I-4, and pharmaceutically acceptable derivatives
thereof, wherein Y is a bond and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0384] In another embodiment, the present invention encompasses compounds
of formula I-4, and pharmaceutically acceptable derivatives thereof,
wherein Y is --CH2-- and all other variables have the same meanings
as set forth above for the compounds of formula I.

[0385] In another embodiment, the present invention encompasses compounds
of formula I-4, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)2-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0386] In another embodiment, the present invention encompasses compounds
of formula I-4, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)3-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0387] In another embodiment, the present invention encompasses compounds
of formula I-4, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)4-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0388] In another embodiment, the present invention encompasses compounds
of formula I-4, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)5-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0389] In another embodiment, the present invention encompasses compounds
of formula I-4, and pharmaceutically acceptable derivatives thereof,
wherein R5 is C1-C6 hydroxyalkyl and all other variables
have the same meanings as set forth above for the compounds of formula I.

[0390] In another embodiment, the invention encompasses the compounds of
formula I-4 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0391] In another embodiment, the invention encompasses the compounds of
formula I-4 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0392] In another embodiment, the invention encompasses the compounds of
formula I-4, and pharmaceutically acceptable derivatives thereof, werein
R5 is --(CH2)rC(O)NRvRvi, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0393] In another embodiment, the invention encompasses the compounds of
formula I-4, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, and all other variables have the
same meanings as set forth above for the compounds of formula I.

[0394] In another embodiment, the invention encompasses the compounds of
formula I-4, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, Rix is arylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms, and the aryl group
is substituted with C1-C6 hydroxyalkyl, and all other variables
have the same meanings as set forth above for the compounds of formula I.

[0395] In another embodiment, the invention encompasses the compounds of
formula I-4, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rC(O)ORix, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0396] In another embodiment, the invention encompasses the compounds of
formula I-4, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)1-6--O--(CH2)0-6-aryl, and all
other variables have the same meanings as set forth above for the
compounds of formula I.

[0397] In another embodiment, the invention encompasses the compounds of
formula I-4, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSRviii, wherein Rviii is aryl or
--C(O)Rx, and all other variables have the same meanings as set
forth above for the compounds of formula I.

[0398] In another embodiment, the compounds of the invention encompass the
compounds of formula I-5:

##STR00020##

[0399] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0400] In other embodiments, the invention encompasses the compounds of
formula I-5, wherein Z is a cyclobutyl group, and all variables have the
same meanings as set forth above for the compounds of formula I, and with
the proviso that when m is 2 and Y is a bond, R5 is not
C1-C6 straight chain alkyl; C3-C6 branched chain
alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; and

[0401] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0402] In some embodiments, the compound of formula I-5 have the formula:

##STR00021##

[0403] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0404] In other embodiments, the invention encompasses the compounds of
formula I-5 having the formula:

##STR00022##

[0405] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I, and with the proviso that when m is 2 and Y is a bond, R5
is not C1-C6 straight chain alkyl; C3-C6 branched
chain alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)Rix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; and

[0406] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0407] In other embodiments, the compounds of formula I-5 have the
formula:

##STR00023##

[0408] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0409] In other embodiments, the invention encompasses the compounds of
I-5 having the formula:

##STR00024##

[0410] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I, and with the proviso that when m is 2 and Y is a bond, R5
is not C1-C6 straight chain alkyl; C3-C6 branched
chain alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; and

[0411] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0412] In yet another embodiment, the present invention encompasses
compounds of formula I-5, and pharmaceutically acceptable derivatives
thereof, wherein Y is a bond and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0413] In another embodiment, the present invention encompasses compounds
of formula I-5, and pharmaceutically acceptable derivatives thereof,
wherein Y is --CH2-- and all other variables have the same meanings
as set forth above for the compounds of formula I.

[0414] In another embodiment, the present invention encompasses compounds
of formula I-5, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)2-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0415] In another embodiment, the present invention encompasses compounds
of formula I-5, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)3-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0416] In another embodiment, the present invention encompasses compounds
of formula I-5, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)4-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0417] In another embodiment, the present invention encompasses compounds
of formula I-5, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)5-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0418] In another embodiment, the present invention encompasses compounds
of formula I-5, and pharmaceutically acceptable derivatives thereof,
wherein R5 is C1-C6 hydroxyalkyl and all other variables
have the same meanings as set forth above for the compounds of formula I.

[0419] In another embodiment, the invention encompasses the compounds of
formula I-5 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0420] In another embodiment, the invention encompasses the compounds of
formula I-5 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0421] In another embodiment, the invention encompasses the compounds of
formula I-5, and pharmaceutically acceptable derivatives thereof, werein
R5 is --(CH2)rC(O)NRvRvi, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0422] In another embodiment, the invention encompasses the compounds of
formula I-5, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, and all other variables have the
same meanings as set forth above for the compounds of formula I.

[0423] In another embodiment, the invention encompasses the compounds of
formula I-5, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rC(O)ORix, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0424] In another embodiment, the invention encompasses the compounds of
formula I-5, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)1-6--O--(CH2)0-6-aryl, and all
other variables have the same meanings as set forth above for the
compounds of formula I.

[0425] In another embodiment, the invention encompasses the compounds of
formula I-5, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSRviii, wherein Rviii is aryl or
--C(O)Rx, and all other variables have the same meanings as set
forth above for the compounds of formula I.

[0426] In some embodiments, the present invention encompasses compounds of
formula I-6:

##STR00025##

[0427] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0428] In other embodiments, the invention encompasses the compounds of
formula I-6, wherein all variables have the same meanings as set forth
above for the compounds of formula I, and with the proviso that when m is
2 and Y is a bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
wherein Rv and Rvi are each independently hydrogen,
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl; --(CH2)rSRviii when
Rviii is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl;
--(CH2)rSO2Rix, (CH2)rSORix or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, C3-C6
cycloalkyl or phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; and

[0429] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0430] In certain embodiments, the compounds of formula I-6 have the
formula:

##STR00026##

[0431] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0432] In other embodiments, the invention encompasses the compounds of
formula I-6 have the formula:

##STR00027##

[0433] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I, and with the proviso that when m is 2 and Y is a bond, R5
is not C1-C6 straight chain alkyl; C3-C6 branched
chain alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; and

[0434] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0435] In other embodiments, the compounds of formula I-6 have the
formula:

##STR00028##

[0436] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I.

[0437] In other embodiments, the invention encompasses compounds of
formula I-6 have the formula:

##STR00029##

[0438] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula I, and with the proviso that when m is 2 and Y is a bond, R5
is not C1-C6 straight chain alkyl; C3-C6 branched
chain alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, C3-C6 cycloalkyl or phenylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; and

[0439] with the proviso that when m is 1 or 3 and Y is a bond, R5 is
not --(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0440] In yet another embodiment, the present invention encompasses
compounds of formula I-6, and pharmaceutically acceptable derivatives
thereof, wherein Y is a bond and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0441] In another embodiment, the present invention encompasses compounds
of formula I-6, and pharmaceutically acceptable derivatives thereof,
wherein Y is --CH2-- and all other variables have the same meanings
as set forth above for the compounds of formula I.

[0442] In another embodiment, the present invention encompasses compounds
of formula I-6, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)2-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0443] In another embodiment, the present invention encompasses compounds
of formula I-6, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)3-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0444] In another embodiment, the present invention encompasses compounds
of formula I-6, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)4-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0445] In another embodiment, the present invention encompasses compounds
of formula I-6, and pharmaceutically acceptable derivatives thereof,
wherein Y is --(CH2)5-- and all other variables have the same
meanings as set forth above for the compounds of formula I.

[0446] In another embodiment, the present invention encompasses compounds
of formula I-6, and pharmaceutically acceptable derivatives thereof,
wherein R5 is C1-C6 hydroxyalkyl and all other variables
have the same meanings as set forth above for the compounds of formula I.

[0447] In another embodiment, the invention encompasses the compounds of
formula I-6 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0448] In another embodiment, the invention encompasses the compounds of
formula I-6 and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rNRvRvi, wherein Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl,
--(CO)Rvii or --SO2Rvii, wherein if one of Rv and
Rvi is --(CO)Rvii or --SO2Rvii, the other is not
--(CO)Rvii or --SO2Rvii, or when Rvi is either
--(CO)Rvii or --SO2Rvii, Rv and Rvii are taken
together to form a 4- to 7-membered ring, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0449] In another embodiment, the invention encompasses the compounds of
formula I-6, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rC(O)NRvRvi, and all other
variables have the same meanings as set forth above for the compounds of
formula I.

[0450] In another embodiment, the invention encompasses the compounds of
formula I-6, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSORix, and all other variables have the
same meanings as set forth above for the compounds of formula I.

[0451] In another embodiment, the invention encompasses the compounds of
formula I-6, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rC(O)Rix, and all other variables have
the same meanings as set forth above for the compounds of formula I.

[0452] In another embodiment, the invention encompasses the compounds of
formula I-6, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)1-6--O--(CH2)0-6-aryl, and all
other variables have the same meanings as set forth above for the
compounds of formula I.

[0453] In another embodiment, the invention encompasses the compounds of
formula I-1 through 1-6 and pharmaceutically acceptable derivatives
thereof, wherein R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl and all other
variables have the same meanng set forth above for the compounds of
formula I.

[0454] In another embodiment, the invention encompasses the compounds of
formula I-6, and pharmaceutically acceptable derivatives thereof, wherein
R5 is --(CH2)rSRviii, wherein Rviii is aryl or
--C(O)Rx, and all other variables have the same meanings as set
forth above for the compounds of formula I.

[0455] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula I is selected from:

##STR00030## ##STR00031## ##STR00032## ##STR00033##

[0456] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula I is selected from:

##STR00034## ##STR00035## ##STR00036##

[0457] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula I is selected from:

##STR00037## ##STR00038## ##STR00039## ##STR00040##

[0458] In another embodiment, the compound of formula I is selected from:

##STR00041## ##STR00042## ##STR00043##

[0459] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula I is selected from:

##STR00044## ##STR00045## ##STR00046## ##STR00047##

[0460] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula I is selected from:

[0462] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula II.

[0463] In another embodiment, the invention encompasses compounds of
formula II, wherein all variables have the same meanings as set forth
above for the compounds of formula II, and with the proviso that when Z'
is a 4- to 6-membered saturated heterocycle, m is 2 and Y is a bond,
R5 is not C1-C6 straight chain alkyl; C3-C6
branched chain alkyl; alkoxyalkyl in which the alkoxy and alkyl portions
each independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi when one of Rv and
Rvi is hydrogen, and the other of Rv and Rvi is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl or when Rv and Rvi are
independently C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl.

[0464] In another embodiment, R1 is H.

[0465] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0466] In another embodiment, R1 is C3-C6 branched chain
alkyl.

[0467] In another embodiment, R1 is allyl.

[0468] In another embodiment, R1 is C3-C6 cycloalkyl.

[0469] In another embodiment, R2 is H.

[0470] In another embodiment, R3 is H.

[0471] In another embodiment, R4 is H.

[0472] In another embodiment, R2, R3 and R4 are each H.

[0473] In another embodiment, m is 1.

[0474] In another embodiment, m is 2.

[0475] In another embodiment, m is 3.

[0476] In another embodiment, n is 1.

[0477] In another embodiment, n is 2.

[0478] In another embodiment, p is 0.

[0479] In another embodiment, p is 1.

[0480] In another embodiment, p is 2.

[0481] In another embodiment, n is 1 and p is 0.

[0482] In one embodiment, Y is --CH2-- and Z' is a four- to
six-membered saturated heterocycle.

[0483] In another embodiment, Y is --CH2-- and Z' is a five- or
six-membered partially unsaturated heterocycle.

[0484] In another embodiment, Y is --CH2CH2-- and Z' is a four-
to six-membered saturated heterocycle.

[0485] In another embodiment, Y is --CH2CH2-- and Z' is a five-
or six-membered partially unsaturated heterocycle.

[0486] In another embodiment, Y is --CH2CH2CH2-- and Z' is
a four- to six-membered saturated heterocycle.

[0487] In another embodiment, Y is --CH2CH2CH2-- and Z' is
a five- or six-membered partially unsaturated heterocycle.

[0488] In another embodiment, Y is --(CH2)4-- and Z' is a four-
to six-membered saturated heterocycle.

[0489] In another embodiment, Y is --(CH2)4-- and Z' is a five-
or six-membered partially unsaturated heterocycle.

[0490] In another embodiment, Y is --(CH2)5-- and Z' is a four-
to six-membered saturated heterocycle.

[0491] In another embodiment, Y is --(CH2)5-- and Z' is a five-
or six-membered partially unsaturated heterocycle.

[0492] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0493] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0494] In another embodiment, m is 1, Y is a bond and Z' is a four- to
six-membered saturated heterocycle.

[0495] In another embodiment, m is 1, Y is a bond and Z' is a five- or
six-membered partially-unsaturated heterocycle.

[0496] In another embodiment, m is 3, Y is a bond and Z' is a four- to
six-membered saturated heterocycle.

[0497] In another embodiment, m is 3, Y is a bond and Z' is a five- or
six-membered partially-unsaturated heterocycle.

[0498] In another embodiment, m is 1 or 3, Y is a bond, Z' is a four- to
six-membered saturated heterocycle or a five- or six-membered
partially-unsaturated heterocycle having at least 3 carbon atoms and if
Z' is a six-membered ring, R5 is in the meta position on said ring
with respect to the pyridine ring.

[0499] In another embodiment, m is 1 or 3, Y is a bond, Z' is a four- to
six-membered saturated heterocycle or a five- or six-membered
partially-unsaturated heterocycle having at least 3 carbon atoms and if
Z' is a six-membered ring, R5 is the para position on said ring with
respect to the pyridine ring.

[0500] In another embodiment, m is 1 or 3, Y is a bond, Z' is a four- to
six-membered saturated heterocycle or a five- or six-membered
partially-unsaturated heterocycle having at least 3 carbon atoms and if
Z' is a six-membered ring, R5 is the ortho position on said ring
with respect to the pyridine ring.

[0501] In another embodiment, Z' is a 2,5-disubstituted tetrahydrofuryl
group.

[0502] In another embodiment, Z' is a 2,4-disubstituted azetidinyl group.

[0503] In another embodiment, R5 is C1-C6 hydroxyalkyl.

[0504] In another embodiment, R5 is alkoxyalkyl with one or two
hydroxyl substitutents and in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms.

[0505] In another embodiment, R5 is hydroxyalkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms.

[0506] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0507] In another embodiment, R5 is aryl.

[0508] In another embodiment, R5 is biaryl.

[0509] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0510] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0511] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0512] In another embodiment, R5 is heteroaryl.

[0513] In another embodiment, R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl and the other of
Rv and Rvi is --(CO)Rvii or --SO2Rvii, and r and
Rvii are as described above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula II.

[0514] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, and r, Rv and Rvi are
as described above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula II.

[0515] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula II.

[0516] In another embodiment, R5 is --(CH2)rSRviii,
wherein Rviii is hydrogen or --C(O)Rx, and r and Rx are as
defined above for the pyridinyl nicotinic acetylcholine receptor ligands
of the formula II.

[0517] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r is an integer ranging from
0 to 5 and Rix is as defined above for the compounds of formula II.

[0518] In another embodiment, R5 is --(CH2)rSORix,
wherein r is an integer ranging from 0 to 5 and Rix is as defined
above for the compounds of formula II.

[0519] In one embodiment, m is 1 or 2, Y is a bond, and Z is a piperidine
ring.

[0520] In another embodiment, m is 1 or 2, Y is a bond, and Z' is a
piperidine ring linked to the pyridine ring by its nitrogen atom.

[0521] In another embodiment, m is 1 or 2, Y is a bond, and Z' is a
piperidine ring linked to the pyridine ring by one of its carbon atoms.

[0522] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperidine
ring, and R5 is in the para position on said piperidine ring with
respect to the pyridine ring.

[0523] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperidine
ring, and R5 is in the meta position on said piperidine ring with
respect to the pyridine ring.

[0524] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperidine
ring, and R5 is in the ortho position on said piperidine ring with
respect to the pyridine ring.

[0525] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperidine
ring, and R5 is alkoxyalkyl in which the alkoxy and alkyl portions
each independently contain from 1 to 6 carbon atoms; arylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; arylalkoxy in which
the alkoxy portion contains from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl; or
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0526] In another embodiment, m is 2, Y is a bond, Z' is a piperidine ring
that is bound to the pyridine ring by its nitrogen atom, R5 is
alkoxyalkyl in which the alkoxy and alkyl portions each independently
contain from 1 to 6 carbon atoms; arylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; arylalkoxy in which the alkoxy portion
contains from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl; or
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl,
R5 is in the para position on said piperidine ring with respect to
the pyridine ring.

[0527] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperidine
ring and R5 is arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; arylalkoxy in which the alkoxy portion contains from 1
to 6 carbon atoms; or --(CH2)1-6--O--(CH2)0-6-aryl,
wherein said aryl portion of R5 is unsubstituted.

[0528] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperidine
ring and R5 is arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; arylalkoxy in which the alkoxy portion contains from 1
to 6 carbon atoms; or --(CH2)1-6--O--(CH2)0-6-aryl,
wherein said aryl portion of R5 is substituted with one or two
substituents selected from C1-C6 hydroxyalkyl; C1-C6
alkoxy; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; and --OH.

[0529] In another embodiment, m is 1 or 2, Y is a bond and Z' is a
piperazine ring.

[0530] In another embodiment, m is 1 or 2, Y is a bond, and Z' is a
piperazine ring linked to the pyridine ring by a nitrogen atom.

[0531] In another embodiment, m is 1 or 2, Y is a bond, and Z' is a
piperazine ring linked to the pyridine ring by one of its carbon atoms.

[0532] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperazine
ring, and R5 is in the para position on said piperazine ring with
respect to the pyridine ring.

[0533] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperazine
ring and R5 is in the meta position on said piperazine ring with
respect to the pyridine ring.

[0534] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperazine
ring and R5 is in the ortho position on said piperazine ring with
respect to the pyridine ring.

[0535] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperazine
ring and R5 is alkoxyalkyl in which the alkoxy and alkyl portions
each independently contain from 1 to 6 carbon atoms; arylalkyl in which
the alkyl portion contains from 1 to 6 carbon atoms; arylalkoxy in which
the alkoxy portion contains from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl; or
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0536] In another embodiment, m is 2, Y is a bond, Z' is a piperazine ring
that is bound to the pyridine ring by its nitrogen atom, R5 is
alkoxyalkyl in which the alkoxy and alkyl portions each independently
contain from 1 to 6 carbon atoms; arylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; arylalkoxy in which the alkoxy portion
contains from 1 to 6 carbon atoms;
--(CH2)1-6--O--(CH2)0-6-aryl; or
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl,
and R5 is in the para position on said piperidine ring with respect
to the pyridine ring.

[0537] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperazine
ring and R5 is arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; arylalkoxy in which the alkoxy portion contains from 1
to 6 carbon atoms; or --(CH2)1-6--O--(CH2)0-6-aryl,
wherein said aryl portion of R5 is unsubstituted.

[0538] In another embodiment, m is 1 or 2, Y is a bond, Z' is a piperazine
ring and R5 is arylalkyl in which the alkyl portion contains from 1
to 6 carbon atoms; arylalkoxy in which the alkoxy portion contains from 1
to 6 carbon atoms; or --(CH2)1-6--O--(CH2)0-6-aryl,
wherein said aryl portion of R5 is substituted with one or two
substituents selected from C1-C6 hydroxyalkyl; C1-C6
alkoxy; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; and --OH.

[0539] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen and
Z' is a monocyclic saturated five- or six-membered heterocycle having at
least one nitrogen atom which is linked to the pyridine ring through a
nitrogen atom.

[0540] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen and
Z' is a saturated azabicycle having 4 to 8 ring carbon atoms and one
carbon to carbon bridge with 0-2 carbon atoms in the bridge and wherein
said saturated azabicycle is linked through its nitrogen atom to the
pyridine ring.

[0541] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen and
Z' is piperidine linked to the pyridine ring through its nitrogen atom
and R5 is on said piperidine ring in the meta or para position with
respect to the pyridine ring and wherein R5 is optionally
substituted as defined in formula I.

[0542] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen and
Z' is a polycyclic heterocycle having as the only hetero atom a single
nitrogen atom in a 5- or 6-membered ring that is saturated except for its
positions of fusion to the aryl ring, and one aryl ring fused to said
heterocycle and said heterocycle is linked to the pyridine ring through
its nitrogen and wherein said R5 is optionally substituted by the
optional substituents defined in formula I.

[0543] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen and
Z' is piperidine linked to the pyridine ring through its nitrogen atom
and R5 is on said piperidine ring in the meta or para position with
respect to the pyridine ring and R5 is selected from the group
consisting of C1-C6 hydroxyalkyl, C1-C6 fluoroalkyl,
arylalkoxy in which the alkoxy portion has 1 to 6 carbon atoms, and
alkoxyalkyl in which the alkoxy and alkyl portions each independently
contain from 1 to 6 carbon atoms, and wherein said R5 is optionally
substituted by the optional substituents defined in formula I.

[0544] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z'
is piperidine linked to the pyridine ring through its nitrogen atom and
R5 is C1-C6 hydroxyalkyl and wherein said R5 is on
the piperidine ring in the meta or para position with respect to the
pyridine ring.

[0545] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, and R4 are each hydrogen, Z'
is linked to the pyridine ring through its nitrogen and R5 is
C1-C6 hydroxyalkyl or alkoxyalkyl in which the alkoxy and alkyl
portions each independently contain from 1 to 6 carbon atoms and wherein
said R5 is on the Z' ring in the meta or para position with respect
to the pyridine ring and wherein said alkoxyalkyl is optionally
substituted with one or two hydroxyl substituents.

[0546] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, Z' is piperidine linked to the pyridine ring through its
nitrogen atom and R5 is alkoxyalkyl in which the alkoxy and alkyl
portions each independently contain from 1 to 6 carbon atoms and said
alkoxyalkyl is optionally substituted with one or two hydroxyl
substituents and wherein R5 is on the piperidine ring in the meta or
para position with respect to the pyridine ring.

[0547] In some embodiments, the present invention encompasses the
compounds of formula II-1:

##STR00053##

[0548] and pharmaceutically acceptable derivatives thereof, wherein A is O
or S, and all other variables have the same meanings as set forth above
for the compounds of formula II.

[0549] In other embodiments, the present invention encompasses the
compounds of formula II-1, wherein A is O or S, and all other variables
have the same meanings as set forth above for the compounds of formula
II, and with the proviso that when m is 2 and Y is a bond, R5 is not
C1-C6 straight chain alkyl; C3-C6 branched chain
alkyl; alkoxyalkyl in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms; C1-C6
fluoroalkyl; phenylalkyl in which the alkyl portion contains from 1 to 6
carbon atoms; --(CH2)rNRvRvi when one of Rv and
Rvi is hydrogen, and the other of Rv and Rvi is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl or C3-C6 cycloalkyl or when Rv and Rvi are
independently C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl.

[0550] In other embodiments, the present invention encompasses the
compounds of formula II-2:

##STR00054##

[0551] and pharmaceutically acceptable derivatives thereof, wherein A is O
or S, and all other variables have the same meanings as set forth above
for the compounds of formula II.

[0552] In other embodiments, the present invention encompasses the
compounds of formula II-3:

##STR00055##

[0553] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as described above for the compounds of
formula II.

[0554] In other embodiments, the present invention encompasses the
compounds of formula II-3, and pharmaceutically acceptable derivatives
thereof, wherein all variables have the same meanings as described above
for the compounds of formula II, and with the proviso that when m is 2
and Y is a bond, R5 is not C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; alkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms;
C1-C6 fluoroalkyl; phenylalkyl in which the alkyl portion
contains from 1 to 6 carbon atoms; --(CH2)rNRvRvi
when one of Rv and Rvi is hydrogen, and the other of Rv
and Rvi is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl or when Rv and
Rvi are independently C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl.

[0555] In other embodiments, the present invention encompasses the
compounds of formula II-4:

##STR00056##

[0556] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as described above for the compounds of
formula II.

[0557] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula II is selected from:

##STR00057##

[0558] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula II is selected from:

[0562] In another embodiment, the invention encompasses pyridinyl
nicotinic acetylcholine receptor ligands of the formula III:

##STR00074##

[0563] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula III.

[0564] In one embodiment, Riv is hydrogen.

[0565] In one embodiment, Riv is C1-C6 straight chain
alkyl.

[0566] In another embodiment, Riv is C3-C6 branched chain
alkyl.

[0567] In another embodiment, Riv is C3-C6 cycloalkyl.

[0568] In another embodiment, Riv is an acyl group having the
formula:

##STR00075##

wherein Ri is C1-C6 straight chain alkyl.

[0569] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 branched chain alkyl.

[0570] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 cycloalkyl.

[0571] In one embodiment, R1 is H.

[0572] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0573] In another embodiment, R1 is C3-C6 branched chain
alkyl.

[0574] In another embodiment, R1 is allyl.

[0575] In another embodiment, R1 is C3-C6 cycloalkyl.

[0576] In another embodiment, R2 is H.

[0577] In another embodiment, R3 is H.

[0578] In another embodiment, R4 is H.

[0579] In another embodiment, R2, R3 and R4 are each H.

[0580] In another embodiment, m is 1.

[0581] In another embodiment, m is 2.

[0582] In another embodiment, m is 3.

[0583] In another embodiment, n is 1.

[0584] In another embodiment, n is 2.

[0585] In another embodiment, p is 0.

[0586] In another embodiment, p is 1.

[0587] In another embodiment, p is 2.

[0588] In another embodiment, n is 1 and p is 0.

[0589] In one embodiment, Y is --CH2-- and Z is C3-C6
cycloalkyl.

[0590] In another embodiment, Y is --CH2-- and Z is a C4-C6
partially unsaturated carbocycle.

[0591] In another embodiment, Y is --CH2CH2-- and Z is
C3-C6 cycloalkyl.

[0592] In another embodiment, Y is --CH2CH2-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0593] In another embodiment, Y is --CH2CH2CH2-- and Z is
C3-C6 cycloalkyl.

[0594] In another embodiment, Y is --CH2CH2CH2-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0595] In another embodiment, Y is --(CH2)4-- and Z is
C3-C6 cycloalkyl.

[0596] In another embodiment, Y is --(CH2)4-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0597] In another embodiment, Y is --(CH2)5-- and Z is
C3-C6 cycloalkyl.

[0598] In another embodiment, Y is --(CH2)5-- and Z is a
C4-C6 partially unsaturated carbocycle.

[0599] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0600] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0601] In another embodiment, m is 1, Y is a bond and Z is C3-C6
cycloalkyl.

[0602] In another embodiment, m is 1, Y is a bond and Z is a
C4-C6 partially unsaturated carbocycle.

[0603] In another embodiment, m is 2, Y is a bond and Z is C3-C6
cycloalkyl.

[0604] In another embodiment, m is 2, Y is a bond and Z is a
C4-C6 partially unsaturated carbocycle.

[0605] In another embodiment, m is 3, Y is a bond and Z is C3-C6
cycloalkyl.

[0606] In another embodiment, m is 3, Y is a bond and Z is a
C4-C6 partially unsaturated carbocycle.

[0607] In another embodiment, m is 1, 2 or 3, Z is C3-C6
cycloalkyl or a C4-C6 partially unsaturated carbocycle, and if
Z is a six-membered ring, R5 is in the meta position on said ring
with respect to Y.

[0608] In another embodiment, m is 1, 2 or 3, Z is C3-C6
cycloalkyl or a C4-C6 partially unsaturated carbocycle, and if
Z is a six-membered ring, R5 is in the para position on said ring
with respect to Y.

[0609] In another embodiment, m is 1, 2 or 3, Z is C3-C6
cycloalkyl or a C4-C6 partially unsaturated carbocycle, and if
Z is a six-membered ring, R5 is in the ortho position on said ring
with respect to Y.

[0610] In another embodiment, R5 is C1-C6 hydroxyalkyl.

[0611] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0612] In another embodiment, R5 is aryl.

[0613] In another embodiment, R5 is biaryl.

[0614] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0615] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0616] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0617] In another embodiment, R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0618] In another embodiment, R5 is heteroaryl.

[0619] In another embodiment, R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl and the other of
Rv and Rvi is --(CO)Rvii or --SO2Rvii, and r and
Rvii are as described above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula III.

[0620] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, and r, Rv and Rvi are
as described above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula III.

[0621] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula III.

[0622] In another embodiment, R5 is --(CH2)rSRviii,
wherein Rviii is hydrogen or C(O)Rx, and r and Rx are as
defined above for the pyridinyl nicotinic acetylcholine receptor ligands
of the formula III.

[0623] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r is an integer ranging from
0 to 5 and Rix is as defined above for the compounds of formula III.

[0624] In another embodiment, R5 is --(CH2)rSORix,
wherein r is an integer ranging from 0 to 5 and Rix is as defined
above for the compounds of formula III.

[0625] In another embodiment, the invention encompasses compounds of
formula III-1:

##STR00076##

[0626] and pharmaceutically acceptable derivates thereof, wherein Riv
is hydrogen, and all other variables have the same meanings as described
above for the compounds of formula III.

[0627] In another embodiment, the invention encompasses compounds of
formula III-1, and pharmaceutically acceptable derivatives thereof,
wherein Riv is C1-C6 straight chain alkyl or
C3-C6 branched chain alkyl, and all other variables have the
same meanings as described above for the compounds of formula III.

[0628] In another embodiment, the invention encompasses compounds of
formula III-1 and pharmaceutically acceptable derivates thereof, wherein
Riv is C3-C6 cycloalkyl, and all other variables have the
same meanings as described above for the compounds of formula III.

[0629] In another embodiment, the invention encompasses compounds of
formula III-1 and pharmaceutically acceptable derivatives thereof,
wherein Riv is an acyl group having the formula:

##STR00077##

Ri is C1-C6 straight chain alkyl, and all other variables
have the same meanings as described above for the compounds of formula
III.

Nicotinic Acetylcholine Receptor Ligands of the Formula IV

[0630] In another embodiment, the invention encompasses pyridinyl
nicotinic acetylcholine receptor ligands of the formula IV:

##STR00078##

[0631] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as defined above for the pyridinyl
nicotinic acetylcholine receptor ligands of the formula IV.

[0632] In one embodiment, Riv is C1-C6 straight chain
alkyl.

[0633] In another embodiment, Riv is C3-C6 branched chain
alkyl.

[0634] In another embodiment, Riv is C3-C6 cycloalkyl.

[0635] In another embodiment, Riv is an acyl group having the
formula:

##STR00079##

wherein Ri is C1-C6 straight chain alkyl.

[0636] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 branched chain alkyl.

[0637] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 cycloalkyl.

[0638] In one embodiment, R1 is H.

[0639] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0640] In another embodiment, R1 is C3-C6 branched chain
alkyl.

[0641] In another embodiment, R1 is allyl.

[0642] In another embodiment, R1 is C3-C6 cycloalkyl.

[0643] In another embodiment, R2 is H.

[0644] In another embodiment, R3 is H.

[0645] In another embodiment, R4 is H.

[0646] In another embodiment, R2, R3 and R4 are each H.

[0647] In another embodiment, m is 1.

[0648] In another embodiment, m is 2.

[0649] In another embodiment, m is 3.

[0650] In another embodiment, n is 1.

[0651] In another embodiment, n is 2.

[0652] In another embodiment, p is 0.

[0653] In another embodiment, p is 1.

[0654] In another embodiment, p is 2.

[0655] In another embodiment, n is 1 and p is 0.

[0656] In another embodiment, Y is --CH2-- and Z' is a four- to
six-membered saturated heterocycle.

[0657] In another embodiment, Y is --CH2-- and Z' is a five- or
six-membered partially-unsaturated heterocycle.

[0658] In another embodiment, Y is --CH2CH2-- and Z' is a four-
to six-membered saturated heterocycle.

[0659] In another embodiment, Y is --CH2CH2-- and Z' is a five-
or six-membered partially-unsaturated heterocycle.

[0660] In another embodiment, Y is --CH2CH2CH2-- and Z' is
a four- to six-membered saturated heterocycle.

[0661] In another embodiment, Y is --CH2CH2CH2-- and Z' is
a five- or six-membered partially-unsaturated heterocycle.

[0662] In another embodiment, Y is --(CH2)4-- and Z' is a four-
to six-membered saturated heterocycle.

[0663] In another embodiment, Y is --(CH2)4-- and Z' is a five-
or six-membered partially-unsaturated heterocycle.

[0664] In another embodiment, Y is --(CH2)5-- and Z' is a four-
to six-membered saturated heterocycle.

[0665] In another embodiment, Y is --(CH2)5-- and Z' is a five-
or six-membered partially-unsaturated heterocycle.

[0666] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0667] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0668] In another embodiment, m is 1, Y is a bond and Z' is a four- to
six-membered saturated heterocycle.

[0669] In another embodiment, m is 1, Y is a bond and Z' is a five- or
six-membered partially-unsaturated heterocycle.

[0670] In another embodiment, m is 1, Y is a bond and Z' is a saturated
azabicycle and wherein said saturated azabicycle is linked through its
nitrogen atom to the pyridine ring.

[0671] In another embodiment of formula II, m is 1 or 2, Y is a bond, n is
1, p is 0, R1, R2, R3, R4, and R5 are each
hydrogen and Z' is a saturated azabicycle having 4 to 8 ring carbon atoms
and one carbon to carbon bridge with 0-2 carbon atoms in the bridge and
wherein said saturated azabicycle is linked through its nitrogen atom to
the pyridine ring.

[0672] In another embodiment, m is 2, Y is a bond and Z' is a four- to
six-membered saturated heterocycle.

[0673] In another embodiment, m is 2, Y is a bond and Z' is a five- or
six-membered partially-unsaturated heterocycle.

[0674] In another embodiment, m is 3, Y is a bond and Z' is a four- to
six-membered saturated heterocycle.

[0675] In another embodiment, m is 3, Y is a bond and Z' is a five- or
six-membered partially-unsaturated heterocycle.

[0676] In another embodiment, m is 1, 2 or 3, Z' is a four- to
six-membered saturated heterocycle or a five- or six-membered
partially-unsaturated heterocycle having at least 3 carbon atoms and if
Z' is a six-membered ring, R5 is in the meta position on said ring
with respect to Y.

[0677] In another embodiment, m is 1, 2 or 3, Z' is a saturated four- to
six-membered heterocycle or a five- or six-membered partially-unsaturated
heterocycle having at least carbon atoms and if Z' is a six-membered
ring, R5 is the para position on said ring with respect to Y.

[0678] In another embodiment, m is 1, 2 or 3, Z' is a saturated four- to
six-membered heterocycle or a five- or six-membered partially-unsaturated
heterocycle having at least 3 carbon atoms and if Z' is a six-membered
ring, R5 is the ortho position on said ring with respect to Y.

[0679] In another embodiment, R5 is C1-C6 hydroxyalkyl.

[0680] In another embodiment, R5 is alkoxyalkyl with one or two
hydroxyl substitutents in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms.

[0681] In another embodiment, R5 is hydroxyalkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms.

[0682] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0683] In another embodiment, R5 is aryl.

[0684] In another embodiment, R5 is biaryl.

[0685] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0686] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0687] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0688] In another embodiment, R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0689] In another embodiment, R5 is heteroaryl.

[0690] In another embodiment, R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen, C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl and the other of
Rv and Rvi is --(CO)Rvii or --SO2Rvii, and r and
Rvii are as described above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula IV.

[0691] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, and r, Rv and Rvi are
as described above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula IV.

[0692] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula IV.

[0693] In another embodiment, R5 is --(CH2)rSRviii,
wherein Rviii is hydrogen or C(O)Rx, and r and Rix are as
defined above for the pyridinyl nicotinic acetylcholine receptor ligands
of the formula IV.

[0694] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r is an integer ranging from
0 to 5 and Rix is as defined above for the compounds of formula IV.

[0695] In another embodiment, R5 is --(CH2)rSORix,
wherein r is an integer ranging from 0 to 5 and Rix is as defined
above for the compounds of formula IV.

[0697] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula V.

[0698] In another embodiment, the invention encompasses the compounds of
formula V, wherein all variables have the same meanings as described
above for the compounds of formula V, and with the proviso that when Z''
is an aryl group, m is 2 and Y is a bond, R5 is not phenylalkyl in
which the alkyl portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSO2Rix or --(CH2)rC(O)Rix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl; and

[0699] with the proviso that when Z'' is an aryl group, m is 1 or 3 and Y
is a bond, R5 is not --(CH2)rNRvRvi when either
Rv and Rvi are hydrogen, or when one of Rv and Rvi is
hydrogen and the other of Rv and Rvi is C1-C6
straight chain alkyl, C3-C6 branched chain alkyl or
C3-C6 cycloalkyl.

[0700] In one embodiment R1 is H.

[0701] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0702] In another embodiment, R1 is allyl.

[0703] In another embodiment, R1 is C3-C6 cycloalkyl.

[0704] In another embodiment, R2 is H.

[0705] In another embodiment, R3 is H.

[0706] In another embodiment, R4 is H.

[0707] In another embodiment, R2, R3 and R4 are each H.

[0708] In another embodiment, one of R2, R3 and R4 is
methyl.

[0709] In another embodiment, m is 1.

[0710] In another embodiment, m is 2.

[0711] In another embodiment, m is 3.

[0712] In another embodiment, n is 1.

[0713] In another embodiment, n is 2.

[0714] In another embodiment, p is 0.

[0715] In another embodiment, p is 1.

[0716] In another embodiment, p is 2.

[0717] In another embodiment, n is 1 and p is 0.

[0718] In another embodiment, R5 is alkoxyalkyl with one or two
hydroxyl substitutents in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms.

[0719] In another embodiment, R5 is hydroxyalkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms.

[0720] In another embodiment, R5 is C1-C6 hydroxyalkyl.

[0721] In another embodiment, R5 is arylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms.

[0722] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0723] In another embodiment, R5 is aryl.

[0724] In another embodiment, R5 is biaryl.

[0725] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0726] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0727] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0728] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0729] In another embodiment, R5 is heteroaryl.

[0730] In another embodiment, R5 is
--(CH2)rNRvRvi, wherein r is an integer ranging from
0 to 5 and Rv and Rvi are each independently C1-C6
straight chain alkyl, C3-C6 branched chain alkyl;
C3-C6 cycloalkyl; --(CO)Rvii; or --SO2Rvii, and
Rvii has the meaning described above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula V.

[0731] In another embodiment R5 is
--(CH2)rNRvRvi, wherein r is an integer ranging from
1 to 5.

[0732] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, wherein r, Rv and Rvi
are as defined above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula V.

[0733] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula V.

[0734] In another embodiment, R5 is --(CH2)rSRviii,
wherein r and Rviii are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula V.

[0735] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r and Rix are as defined
above for the pyridinyl nicotinic acetylcholine receptor ligands of the
formula V.

[0736] In another embodiment, R5 is --(CH2)rSORix,
wherein r and Rix are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula V.

[0737] In another embodiment, Z'' is phenyl and R5 is in the meta
position on said phenyl ring in relation to the pyridine ring.

[0738] In another embodiment, Y is a bond and Z'' is an aryl group.

[0739] In another embodiment, Y is a bond and Z'' is a phenyl group.

[0740] In another embodiment, Y is a bond, Z'' is a phenyl group, and
R5 is in the para position on said ring with respect to the pyridine
ring.

[0741] In another embodiment, Y is a bond, Z'' is a phenyl group and
R5 is in the meta position on said ring with respect to the pyridine
ring.

[0742] In another embodiment, Y is a bond, Z'' is a phenyl group, and
R5 is in the ortho position on said ring with respect to the
pyridine ring.

[0743] In another embodiment, Y is a bond, Z'' is a phenyl group and
R5 is C1-C6 hydroxyalkyl.

[0744] In another embodiment, Y is --CH2-- and Z'' is an aryl group.

[0745] In another embodiment, Y is --CH2CH2-- and Z'' is an aryl
group.

[0746] In another embodiment, Y is --CH2--, Z'' is a phenyl group and
R5 is C1-C6 alkoxy that is in the meta position on said
ring with respect to Y.

[0747] In another embodiment, Y is --CH2CH2--, Z'' is phenyl and
R5 is C1-C6 alkoxy that is in the meta position on said
ring with respect to Y.

[0748] In another embodiment, Y is --CH2CH2CH2-- and Z'' is
an aryl group.

[0749] In another embodiment, Y is --(CH2)4-- and Z'' is an aryl
group.

[0750] In another embodiment, Y is --(CH2)5-- and Z'' is an aryl
group.

[0751] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0752] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0753] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, Z'' is a phenyl group, and R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen and the other is --SO2Rvii, and Rvii is
C1-C6 straight chain alkyl or aryl, wherein R5 is in the
meta position on said ring with respect to Y.

[0754] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, Z'' is a phenyl group, R5 is
--(CH2)rNRvRvi, Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl, wherein R5 is in the para
position with respect to Y, and r is an integer ranging from 0 to 5.

[0755] In another embodiment, Z'' is phenyl that is substituted with one
or two substituents selected from C1-C6 straight chain alkyl;
C3-C6 branched chain alkyl; C1-C6 fluoroalkyl;
C1-C6 alkoxy; alkoxyalkyl in which the alkoxy and alkyl
portions each independently contain from 1 to 6 carbon atoms;
alkoxyalkoxy in which the alkoxy portions each independently contain from
1 to 6 carbon atoms; F; --OH; --NH2; C1-C6 alkylthio;
CF3; C1-C6 monoalkylamino; C1-C6 dialkylamino;
carboxyl; and C2-C6 alkoxycarbonyl.

[0756] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, Z'' is phenyl and R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen, and the other is C1-C6 straight chain alkyl, and
Rv and Rvi are taken together to form a 4- to 7-membered ring,
and wherein R5 is in the meta position on said ring with respect to
Y.

[0757] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, Z'' is phenyl and R5 is
--(CH2)rNRvRvi, wherein one of Rv and Rvi
is hydrogen, and the other is C1-C6 straight chain alkyl, and
Rv and Rvi are taken together to form a 4- to 7-membered ring,
and wherein R5 is in the ortho position on said ring with respect to
Y.

[0758] In another embodiment, the invention encompasses compounds of
formula V-1:

##STR00081##

[0759] and pharmaceutically acceptable derivatives thereof, wherein
R5 is C1-C6 hydroxyalkyl and all other variables have the
same meanings as set forth above for the compounds of formula V.

[0760] In another embodiment, the invention encompasses compounds of
formula V-1, and pharmaceutically acceptable derivatives thereof, wherein
all variables have the meanings as set forth above for the compounds of
formula IXI, and with the proviso that when m is 2 and Y is a bond,
R5 is not phenylalkyl in which the alkyl portion contains from 1 to
6 carbon atoms; --(CH2)rNRvRvi when Rv and
Rvi are each independently hydrogen, C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSRviii when Rviii is
C1-C6 straight chain alkyl, C3-C6 branched chain
alkyl, or C3-C6 cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl or C3-C6 cycloalkyl; and

with the proviso that when m is 1 or 3 and Y is a bond, R5 is not
--(CH2)rNRvRvi when both Rv and Rvi are
hydrogen, or when one of Rv and Rvi is hydrogen and the other
of Rv and Rvi is C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0761] In another embodiment, the invention encompasses the compounds of
formula V-1, wherein R5 is in the meta position on the phenyl group
with respect to Y.

[0762] In another embodiment, the invention encompasses the compounds of
formula V-1, wherein R5 is in the para position on the phenyl group
with respect to Y.

[0763] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen and Z'' is
aryl.

[0764] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen and Z'' is
phenyl.

[0765] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen, Z'' is
phenyl and R5 is selected from the group consisting of
C1-C6 hydroxyalkyl, hydroxyalkoxyalkyl in which the alkoxy and
alkyl portions each independently contain from 1 to 6 carbon atoms,
arylalkoxy in which the alkoxy portion has from 1 to 6 carbon atoms,
--(CH2)1-6--O--(CH2)0-6-aryl and
--(CH2)1-6--O--(CH2)0-6-heteroaryl and wherein
R5 is on the Z'' phenyl ring in the meta position with respect to
the pyridine ring.

[0766] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen, Z'' is
phenyl and R5 is hydroxyalkoxyalkyl in which the alkoxy and alkyl
portions each independently contain from 1 to 6 carbon atoms and wherein
said R5 is on the phenyl ring in the meta position with respect to
the pyridine ring.

[0767] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen, Z'' is
phenyl and R5 is C1-C6 hydroxyalkyl and wherein said
R5 is on the Z'' phenyl ring in the meta position with respect to
the pyridine ring.

[0768] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen, Z'' is
phenyl and R5 is arylalkoxy in which the alkoxy portion has from 1
to 6 carbon atoms and wherein R5 is on the phenyl ring in the meta
position with respect to the pyridine ring.

[0769] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen, Z'' is
phenyl and R5 is --(CH2)1-6--O--(CH2)0-6-aryl
and wherein R5 is on the Z'' phenyl ring in the meta position with
respect to the pyridine ring and wherein said R5 is optionally
substituted by the optional substituents defined in formula I.

[0770] In another embodiment of formula V, m is 1, Y is a bond, n is 1, p
is 0, R1, R2, R3, and R4 are each hydrogen, Z'' is
phenyl and R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl and wherein
R5 is on the Z'' phenyl ring in the meta position with respect to
the pyridine ring and wherein said R5 is optionally substituted
defined in formula I.

[0771] In another embodiment, the invention encompasses the compounds of
formula V-2:

##STR00082##

[0772] and pharmaceutically acceptable derivatives thereof, wherein
R5 is selected from arylalkyl in which the alkyl portion contains
from 1 to 6 carbon atoms; arylalkoxy in which the alkoxy portion contains
from 1 to 6 carbon atoms; aryl, biaryl, heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms; heteroaryl;
--(CH2)1-6--O--(CH2)0-6-aryl;
--(CH2)1-6--O--(CH2)0-6-heteroaryl;
--(CH2)rC(O)NRvRvi; --(CH2)rC(O)ORix;
--(CH2)rSRviii; --(CH2)rSO2Rix or
--(CH2)rSORix, and all other variables have the same
meanings as set forth above for the compounds of formula V.

[0773] In some embodiments, the compound of formula V is selected from:

##STR00083## ##STR00084## ##STR00085##

[0774] In other embodiments, the compound of formula V is selected from:

##STR00086## ##STR00087##

[0775] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand of the formula V is selected from:

[0777] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as defined above for the pyridinyl
nicotinic acetylcholine receptor ligands of the formula VI.

[0778] In some embodiments, the invention encompasses the compounds of
formula VI, and pharmaceutically acceptable derivatives thereof, wherein
all variables have the same meanings as set forth above for the compounds
of formula VI, and with the proviso that when Z''' is a heteroaryl group,
m is 2 and Y is a bond, R5 is not phenylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl; with the proviso
that when Z''' is pyridine, m is 2, and Y is a bond, R5 is not
--CH2OH; and with the proviso that Z''' is a heteroaryl group, when
m is 1 or 3 and Y is a bond, R5 is not
--(CH2)rNRvRvi when both Rv and Rvi are
hydrogen, or when one of Rv and Rvi is hydrogen and the other
of Rv and Rvi is C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0779] In one embodiment R1 is H.

[0780] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0781] In another embodiment, R1 is allyl.

[0782] In another embodiment, R1 is C3-C6 cycloalkyl.

[0783] In another embodiment, R2 is H.

[0784] In another embodiment, R3 is H.

[0785] In another embodiment, R4 is H.

[0786] In another embodiment, R2, R3 and R4 are each H.

[0787] In another embodiment, one of R2, R3 and R4 is
methyl.

[0788] In another embodiment, m is 1.

[0789] In another embodiment, m is 2.

[0790] In another embodiment, m is 3.

[0791] In another embodiment, n is 1.

[0792] In another embodiment, n is 2.

[0793] In another embodiment, p is 0.

[0794] In another embodiment, p is 1.

[0795] In another embodiment, p is 2.

[0796] In another embodiment, n is 1 and p is 0.

[0797] In another embodiment, R5 is alkoxyalkyl with one or two
hydroxyl substitutents and in which the alkoxy and alkyl portions each
independently contain from 1 to 6 carbon atoms.

[0798] In another embodiment, R5 is hydroxyalkoxyalkyl in which the
alkoxy and alkyl portions each independently contain from 1 to 6 carbon
atoms.

[0799] In another embodiment, R5 is C1-C6 hydroxyalkyl.

[0800] In another embodiment, R5 is arylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms.

[0801] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0802] In another embodiment, R5 is aryl.

[0803] In another embodiment, R5 is biaryl.

[0804] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0805] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0806] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0807] In another embodiment, R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0808] In another embodiment, R5 is heteroaryl.

[0809] In another embodiment, R5 is
--(CH2)rNRvRvi, wherein r is an integer ranging from
0 to 5 and Rv and Rvi are each independently C1-C6
straight chain alkyl, C3-C6 branched chain alkyl;
C3-C6 cycloalkyl; --(CO)Rvii; or --SO2Rvii, and
Rvii has the meaning described above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VI.

[0810] In another embodiment R5 is
--(CH2)rNRvRvi, wherein r is an integer ranging from
1 to 5.

[0811] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, wherein r, Rv and Rvi
are as defined above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula VI.

[0812] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula VI.

[0813] In another embodiment, R5 is --(CH2)rSRviii,
wherein r and Rviii are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VI.

[0814] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r and Rix are as defined
above for the pyridinyl nicotinic acetylcholine receptor ligands of the
formula VI.

[0815] In another embodiment, R5 is --(CH2)rSORix,
wherein r and Rix are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VI.

[0816] In another embodiment, Y is a bond.

[0817] In another embodiment, R5 is in the para position with respect
to Y.

[0818] In another embodiment, R5 is in the meta position with respect
to Y.

[0819] In another embodiment, R5 is in the ortho position with
respect to Y.

[0820] In another embodiment, Z''' is a 2,5-disubstituted pyridinyl group.

[0821] In another embodiment, Z''' is a 2,4-disubstituted pyridinyl group.

[0822] In another embodiment, Z''' is a 3,7-disubstituted 1H-indolyl
group.

[0823] In another embodiment, Z''' is a 2,5-disubstituted thienyl group.

[0824] In another embodiment, Z''' is a 3,5-disubstituted isoxazolyl
group.

[0825] In another embodiment, Y is --CH2-- and Z''' is a heteroaryl
group.

[0826] In another embodiment, Y is --CH2CH2-- and Z''' is a
heteroaryl group.

[0827] In another embodiment, Y is --CH2CH2CH2-- and Z'''
is a heteroaryl group.

[0828] In another embodiment, Y is --(CH2)4-- and Z''' is a
heteroaryl group.

[0829] In another embodiment, Y is --(CH2)5-- and Z''' is a
heteroaryl group.

[0830] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0831] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0832] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, Z''' is a pyridinyl group, and R5 is
C1-C6 hydroxyalkyl, wherein R5 is in the para position on
said Z''' group with respect to Y.

[0833] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, Z''' is a 1H-indol-3-yl group, and R5 is
--(CH2)rNRvRvi, Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl.

[0834] In another embodiment, Y is a bond, Z''' is a pyridinyl group, and
R5 (CH2)rC(O)NRvRvi, wherein r is an integer
ranging between 0 and 5, and Rv and Rvi are each independently
C1-C6 straight chain alkyl.

[0835] In another embodiment, Y is a bond, Z''' is a thienyl group, and
R5 is 2-(methoxycarbonyl)ethyl.

[0836] In another embodiment, Y is a bond, Z''' is an isoxazolyl group,
and R5 is C1-C6 hydroxyalkyl.

[0837] In one embodiment, the invention encompasses compounds of formula
VI-1:

##STR00102##

[0838] and pharmaceutically acceptable derivatives thereof, wherein one or
two of A, B, C, D and E is nitrogen and the other members of the cyclic
aromatic ring are carbon atoms, R5 is bound to a carbon atom, and
all other variables have the same meanings as set forth above for the
compounds of formula VI.

[0839] In another embodiment, the invention encompasses compounds of
formula VI-1, wherein one or two of A, B, C, D and E is nitrogen, R5
is bound to a carbon atom, and all other variables have the same meanings
as set forth above for the compounds of formula VI, and with the proviso
that when m is 2 and Y is a bond, R5 is not phenylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl; with the proviso
that when m is 2, Y is a bond and Z''' is pyridine, R5 is not
--CH2OH; and with the proviso that when m is 1 or 3 and Y is a bond,
R5 is not --(CH2)rNRvRvi when both Rv and
Rvi are hydrogen, or when one of Rv and Rvi is hydrogen
and the other of Rv and Rvi is C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl.

[0840] In another embodiment, the invention encompasses compounds of
formula VI-1 wherein A is N, B, C, D and E are each carbon, R5 is
bound to the carbon atom at position E, and all other variables have the
same meanings as set forth above for the compounds of formula VI.

[0841] In other embodiments, the invention emcompasses compounds of
formula VI-1 wherein m is 1, R5 is C1-C6 hydroxyalkyl and
is bound to a carbon atom, and all other variables have the same meanings
as set forth above for the compounds of formula VI.

[0842] In still other embodiments, the invention encompasses compounds of
formula VI-1 wherein Y is --(CH2)q and q is an integer ranging
from 1 to 5, R5 is C1-C6 hydroxyalkyl and is bound to a
carbon atom, and all other variables have the same meanings as set forth
above for the compounds of formula VI.

m is 1, Y is --(CH2)q and q is an integer ranging from 1 to 5,
R5 is C1-C6 hydroxyalkyl and is bound to a carbon atom,
and all other variables have the same meanings as set forth above for the
compounds of formula VI.

[0845] In another embodiment, the invention encompasses compounds of
formula VI-2:

##STR00105##

[0846] and pharmaceutically acceptable derivatives thereof, wherein A is O
or S, and all other variables have the same meanings as set forth above
for the compounds of formula VI.

[0847] In other embodiments, the invention encompasses compounds of
formula VI-2, and pharmaceutically acceptable derivatives thereof,
wherein A is O or S, and all other variables have the same meanings as
set forth above for the compounds of formula X, and with the proviso that
when m is 2 and Y is a bond, R5 is not phenylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl; and with the proviso
that when m is 1 or 3 and Y is a bond, R5 is not
--(CH2)rNRvRvi when both Rv and Rvi are
hydrogen, or when one of Rv and Rvi is hydrogen and the other
of Rv and Rvi is C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0848] In another embodiment, the invention encompasses compounds of
formula VI-3:

##STR00106##

[0849] and pharmaceutically acceptable derivatives thereof, wherein one of
A and B is oxygen and the other is nitrogen, wherein if A is oxygen and B
is nitrogen, then there is a double bond between carbon atoms 1 and 5 and
between carbon atom 4 and B, and wherein if B is oxygen and A is
nitrogen, then there is a double bond between carbon atom 1 and A, and
between carbon atoms 4 and 5, and wherein all other variables have the
same meanings as set forth above for the compounds of formula VI.

[0850] In another embodiment, the invention encompasses compounds of
formula VI-3, and pharmaceutically acceptable derivatives thereof,
wherein one of A and B is oxygen and the other is nitrogen, wherein if A
is oxygen and B is nitrogen, then there is a double bond between carbon
atoms 1 and 5 and between carbon atom 4 and B, and wherein if B is oxygen
and A is nitrogen, then there is a double bond between carbon atom 1 and
A, and between carbon atoms 4 and 5, and wherein all other variables have
the same meanings as set forth above for the compounds of formula X, and
with the proviso that when m is 2 and Y is a bond, R5 is not
phenylalkyl in which the alkyl portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSO2Rix,
--(CH2)rSORix or --(CH2)rC(O)ORix when
Rix is C1-C6 straight chain alkyl, C3-C6
branched chain alkyl, or C3-C6 cycloalkyl; and with the proviso
that when m is 1 or 3 and Y is a bond, R5 is not
--(CH2)rNRvRvi when both Rv and Rvi are
hydrogen, or when one of Rv and Rvi is hydrogen and the other
of Rv and Rvi is C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

[0851] In another embodiment, the invention encompasses compounds of
formula VI-4:

##STR00107##

[0852] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula VI.

[0853] In another embodiment, the invention encompasses compounds of
formula VI-4, wherein all variables have the same meanings as set forth
above for the compounds of formula VI, and with the proviso that when m
is 2 and Y is a bond, R5 is not phenylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms;
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl;
--(CH2)rSRviii when Rviii is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl; --(CH2)rSO2Rix, --(CH2)rSOR' or
--(CH2)rC(O)ORix when Rix is C1-C6 straight
chain alkyl, C3-C6 branched chain alkyl, or C3-C6
cycloalkyl; and with the proviso that when m is 1 or 3 and Y is a bond,
R5 is not --(CH2)rNRvRvi when both Rv and
Rvi are hydrogen, or when one of Rv and Rvi is hydrogen
and the other of Rv and Rvi is C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl.

[0854] In another embodiment, the compound of formula VI is selected from:

##STR00108##

[0855] In another embodiment, the compound of formula VI is selected from:

##STR00109## ##STR00110## ##STR00111## ##STR00112##

Nicotinic Acetylcholine Receptor Ligands of the Formula VII

[0856] In another embodiment, the invention encompasses pyridinyl
nicotinic acetylcholine receptor ligands of the formula VII:

##STR00113##

[0857] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula VII.

[0858] In one embodiment, Riv is hydrogen.

[0859] In another embodiment, Riv is C1-C6 straight chain
alkyl.

[0860] In another embodiment, Riv is C3-C6 branched chain
alkyl.

[0861] In another embodiment Riv is C3-C6 cycloalkyl.

[0862] In another embodiment, Riv is an acyl group having the
formula:

##STR00114##

wherein Ri is C1-C6 straight chain alkyl.

[0863] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 branched chain alkyl.

[0864] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 cycloalkyl.

[0865] In one embodiment R1 is H.

[0866] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0867] In another embodiment, R1 is allyl.

[0868] In another embodiment, R1 is C3-C6 cycloalkyl.

[0869] In another embodiment, R2 is H.

[0870] In another embodiment, R3 is H.

[0871] In another embodiment, R4 is H.

[0872] In another embodiment, R2, R3 and R4 are each H.

[0873] In another embodiment, m is 1.

[0874] In another embodiment, m is 2.

[0875] In another embodiment, m is 3.

[0876] In another embodiment, n is 1.

[0877] In another embodiment, n is 2.

[0878] In another embodiment, p is 0.

[0879] In another embodiment, p is 1.

[0880] In another embodiment, p is 2.

[0881] In another embodiment, n is 1 and p is 0.

[0882] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi, wherein r, Rv and Rvi
are as defined above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula VII.

[0883] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula VII.

[0884] In another embodiment, R5 is --(CH2)rSRviii,
wherein r and Rviii are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VII.

[0885] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r and Rix are as defined
above for the pyridinyl nicotinic acetylcholine receptor ligands of the
formula VII.

[0886] In another embodiment, R5 is --(CH2)rSORix,
wherein r and Rix are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VII.

[0889] In another embodiment R5 is alkoxyalkyl wherein the alkyl and
alkoxy portions independently contain from 1 to 6 carbon atoms.

[0890] In another embodiment, R5 is C1-C6 fluoroalkyl.

[0891] In another embodiment, R5 is arylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms.

[0892] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0893] In another embodiment, R5 is aryl.

[0894] In another embodiment, R5 is heteroaryl.

[0895] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0896] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0897] In another embodiment, R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0898] In another embodiment R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0899] In another embodiment, Y is a bond and Z' is an aryl group.

[0900] In another embodiment, Y is a bond and Z' is a phenyl group.

[0901] In another embodiment, Z'' is a phenyl group, and R5 is in the
para position on said ring with respect to Y.

[0902] In another embodiment, Z'' is a phenyl group and R5 is in the
meta position on said ring with respect to Y.

[0903] In another embodiment, Z'' is a phenyl group, and R5 is in the
ortho position on said ring with respect to Y.

[0904] In another embodiment, Y is --CH2-- and Z'' is an aryl group.

[0905] In another embodiment, Y is --CH2CH2-- and Z'' is an aryl
group.

[0906] In another embodiment, Y is --CH2CH2--, Z'' is phenyl and
R5 is C1-C6 alkoxy.

[0907] In another embodiment, Y is --CH2CH2CH2-- and Z'' is
an aryl group.

[0908] In another embodiment, Y is --(CH2)4-- and Z'' is an aryl
group.

[0909] In another embodiment, Y is --(CH2)5-- and Z'' is an aryl
group.

[0910] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0911] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

[0912] In another embodiment, Y is a bond or CH2--, Z'' is phenyl and
R5 is C1-C6 alkoxy, wherein R5 is in the meta
position on said ring with respect to the pyridine ring.

[0913] In another embodiment, Y is a bond, Z'' is phenyl and R5 is
--(CH2)rNRvRvi wherein one of Rv and Rvi is
hydrogen, and the other is --(CO)Rvii, Rv and Rvi are
taken together to form a 4- to 7-membered ring and Rvii is as
described above for the compounds of formula VII, wherein R5 is in
the meta position on said ring with respect to the pyridine ring.

[0914] In another embodiment, the invention encompasses compounds of
formula VII-1:

##STR00115##

[0915] and pharmaceutically acceptable derivatives thereof, wherein all
variables have the same meanings as set forth above for the compounds of
formula VII.

[0916] In another embodiment, the invention encompasses compounds of
formula VII-1, wherein R5 is in the meta position on the phenyl ring
with respect to Y.

[0917] In another embodiment, the invention encompasses compounds of
formula VII-1, wherein R5 is in the para position on the phenyl ring
with respect to Y.

[0918] In another embodiment, the compound of formula VII is selected
from:

##STR00116##

Nicotinic Acetylcholine Receptor Ligands of the Formula VIII

[0919] In another embodiment, the invention encompasses pyridinyl
nicotinic acetylcholine receptor ligands of the formula VIII:

##STR00117##

[0920] and pharmaceutically acceptable derivatives thereof, wherein all
variables are as defined above for the pyridinyl nicotinic acetylcholine
receptor ligands of the formula VIII.

[0921] In one embodiment, Riv is hydrogen.

[0922] In another embodiment, Riv is C1-C6 straight chain
alkyl.

[0923] In another embodiment, Riv is C3-C6 branched chain
alkyl.

[0924] In another embodiment Riv is C3-C6 cycloalkyl.

[0925] In another embodiment, Riv is an acyl group having the
formula:

##STR00118##

wherein Ri is C1-C6 straight chain alkyl.

[0926] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 branched chain alkyl.

[0927] In another embodiment, Riv is an acyl group as shown above and
Ri is C3-C6 cycloalkyl.

[0928] In one embodiment R1 is H.

[0929] In another embodiment, R1 is C1-C6 straight chain
alkyl.

[0930] In another embodiment, R1 is allyl.

[0931] In another embodiment, R1 is C3-C6 cycloalkyl.

[0932] In another embodiment, R2 is H.

[0933] In another embodiment, R3 is H.

[0934] In another embodiment, R4 is H.

[0935] In another embodiment, R2, R3 and R4 are each H.

[0936] In another embodiment, m is 1.

[0937] In another embodiment, m is 2.

[0938] In another embodiment, m is 3.

[0939] In another embodiment, n is 1.

[0940] In another embodiment, n is 2.

[0941] In another embodiment, p is 0.

[0942] In another embodiment, p is 1.

[0943] In another embodiment, p is 2.

[0944] In another embodiment, n is 1 and p is 0.

[0945] In another embodiment, R5 is
--(CH2)rC(O)NRvRvi wherein r, Rv and Rvi
are as defined above for the pyridinyl nicotinic acetylcholine receptor
ligands of the formula VIII.

[0946] In another embodiment, R5 is --(CH2)rC(O)ORix,
and r and Rix have the same meanings as set forth above for the
compounds of formula VIII.

[0947] In another embodiment, R5 is --(CH2)rSRviii,
wherein r and Rviii are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VIII.

[0948] In another embodiment, R5 is
--(CH2)rSO2Rix, wherein r and Rix are as defined
above for the pyridinyl nicotinic acetylcholine receptor ligands of the
formula VIII.

[0949] In another embodiment, R5 is --(CH2)rSORix,
wherein r and Rix are as defined above for the pyridinyl nicotinic
acetylcholine receptor ligands of the formula VIII.

[0952] In another embodiment R5 is alkoxyalkyl wherein the alkyl and
alkoxy portions independently contain from 1 to 6 carbon atoms.

[0953] In another embodiment, R5 is C1-C6 fluoroalkyl.

[0954] In another embodiment, R5 is arylalkyl in which the alkyl
portion contains from 1 to 6 carbon atoms.

[0955] In another embodiment, R5 is arylalkoxy in which the alkoxy
portion contains from 1 to 6 carbon atoms.

[0956] In another embodiment, R5 is aryl.

[0957] In another embodiment, R5 is heteroaryl.

[0958] In another embodiment, R5 is heteroarylalkyl in which the
alkyl portion contains from 1 to 6 carbon atoms.

[0959] In another embodiment, R5 is
--(CH2)1-6--O--(CH2)0-6-aryl.

[0960] In another embodiment, R5 is
--(CH2)0-6--O--(CH2)0-6--C3-C6 cycloalkyl.

[0961] In another embodiment R5 is
--(CH2)1-6--O--(CH2)0-6-heteroaryl.

[0962] In another embodiment, Y is a bond and Z''' is a heteroaryl group.

[0963] In another embodiment, Z''' is a heteroaryl group and R5 is in
the para position on said ring with respect to Y.

[0964] In another embodiment, Z''' is a heteroaryl group and R5 is in
the meta position on said ring with respect Y.

[0965] In another embodiment, Z''' is a heteroaryl group and R5 is in
the ortho position with respect to Y.

[0966] In another embodiment, Y is --CH2-- and Z''' is a heteroaryl
group.

[0967] In another embodiment, Y is --CH2CH2-- and Z''' is a
heteroaryl group.

[0968] In another embodiment, Y is --CH2CH2CH2-- and Z'''
is a heteroaryl group.

[0969] In another embodiment, Y is --(CH2)4-- and Z''' is a
heteroaryl group.

[0970] In another embodiment, Y is --(CH2)5-- and Z''' is a
heteroaryl group.

[0971] In another embodiment, Y is unsubstituted --(CH2)q-- and
q is an integer ranging from 1 to 5.

[0972] In another embodiment, Y is --(CH2)q--, q is an integer
ranging from 1 to 5, and Y is substituted with one or two groups
independently selected from methyl, ethyl, propyl, isopropyl, and
cyclopropyl.

Methods of Synthesis

[0973] Syntheses of compounds according to the invention can be
accomplished by the reactions described below. In some embodiments, the
present invention includes novel intermediates for the synthesis of
nicotinic acetylcholine receptor ligands of the invention, some of which
are shown below.

[0975] This synthetic sequence is depicted in Scheme 1a.
3-(Benzyloxy)-5-bromopyridine was prepared by a procedure reported in the
literature (Zhu, G.-D. et al., Bioorg. Med. Chem. Lett. 2006, 16,
3150-3155) from 3,5-dibromopyridine. A recently reported variant of the
Stille coupling reaction (Cui, X.; Zhou, Y.; Wang, N.; Liu, L.; Guo,
Q.-X. Tetrahedron Lett. 2007, 48, 163-167) furnished the
α,β-unsaturated ester, which was hydrolyzed to the free acid.
For small-scale reactions, this acid could be transformed into its acid
chloride hydrochloride, which was reacted with N,O-dimethylhydroxylamine
hydrochloride in the presence of an excess of triethylamine to yield the
α,β-unsaturated Weinreb amide. The need to control the
exotherm during acid chloride formation at larger scale by cooling
resulted in incomplete conversion of the poorly soluble acid into the
poorly soluble acid chloride hydrochloride. It was in this case
advantageous to couple acid and N,O-dimethylhydroxylamine hydrochloride
by means of a standard peptide coupling reagent, the water-soluble
carbodiimide EDCI. A large number of alternative amide forming/peptide
coupling reagents are known in the literature, and it is likely that many
of these are also of utility in this reaction.

[0976] The cyclopropanation of α,β-unsaturated esters with the
Corey ylide [Me2S(O)=CH2, generated in situ from
Me3S(O)+ I.sup.- and NaH) is a long-established reaction
(Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353-1364) but
tends to give rather low yields (for example: Gooden, D. M. et al.
Bioorg. Med. Chem. Lett. 2008, 18, 3047-3051). This was found to be the
case when the reaction was applied to the α,β-unsaturated
ester of Scheme 1a. On the other hand, α,β-unsaturated Weinreb
amides have been shown to undergo this cyclopropanation efficiently (Toy,
P. H. et al. J. Org. Chem. 1997, 62, 9114-9122). In accordance with this
literature report, the above α,β-unsaturated Weinreb amide was
transformed into the racemic cyclopropane in good yield. Sequential
reduction with diisobutylaluminum hydride to the aldehyde and further
with NaBH4 to the primary alcohol proceeded efficiently. The
enantiomers of this compound were resolved by HPLC on the chiral
stationary phase, Chiralpak® AD (Chiral Technologies, Inc.) with
methanol as the eluent.

[0978] This approach (Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C.
J. Am. Chem. Soc. 1998, 120, 11943-11952) is inherently shorter than the
one shown in Scheme 1a, but gave low yields and optical purities.
Nevertheless, the completion of both sequences enabled the establishment
of the absolute configuration of the individual enantiomers prepared by
racemate resolution, since the generic stereochemical outcome of the
asymmetric Simmons-Smith reaction is known. From the
α,β-unsaturated ester of Scheme 1a, the allylic alcohol was
synthesized via reduction with diisobutylaluminum hydride. While
Charette's protocol usually furnishes good yields of cyclopropanes, the
present case was complicated by the presence of the pyridine ring. In
order to avoid this interference, triethylborane was added as a
complexing agent for the pyridine nitrogen. The improvement in yield was,
however, rather minor.

1c. Installation of the Azetidine Moiety and Deprotection

##STR00121##

[0980] To prevent self-reactivity during the Mitsunobu reaction, the
hydroxyl group of (1S,2S)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethanol
was acylated with isobutyric anhydride (alternatively with acetic
anhydride), and then the phenolic hydroxyl deprotected by hydrogenolysis.
Coupling of the hydroxypyridine intermediate with
1-(tert-butoxycarbonyl)-2(S)-azetidinylmethanol (Chu, W. et al. J. Med.
Chem. 2005, 48, 7637-7647) was performed under modified Mitsunobu
conditions (Tsunoda, T.; Yamamiya, Y.; Ito, S.
1,1'-(Azodicarbonyl)dipiperidine-tributylphosphine, a new reagent system
for Mitsunobu reaction. Tetrahedron Lett. 1993, 34, 1639-1642) to yield
the protected form of the final product. Initial removal of the
isobutyrate with NaOMe, followed by acid treatment to cleave the Boc
group furnished
(1S,2S)-2-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]cyclopropylmethanol as
its hydrochloride.

[0984] This compound was prepared according to Scheme 3. The starting
alcohol was activated as its tosylate and the tosyloxy group substituted
by fluoride anion. Acidic deprotection of the resulting fluoride yielded
the target compound.

[0986] This compound was prepared according to Scheme 4. Chain extension
of the starting alcohol by two carbon atoms was achieved in three steps.
First, oxidation of with activated dimethylsulfoxide led to the aldehyde.
Next, a Wittig reaction with Ph3P═CHCOOMe introduced the
requisite two carbon atoms. Lastly, the C═C double bond and the ester
function were reduced simultaneously with lithium borohydride. Acidic
deprotection of the protected, homologated alcohol yielded the target
compound.

[0990] This compound was prepared according to Scheme 6. This sequence
corresponds to the final two steps in Scheme 2 for the synthesis of the
diastereomer having the opposite configuration at its two asymmetric
cyclopropane carbon atoms.

[0994] This compound may be prepared according to Scheme 8. Standard
Stille coupling of
3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine
(Scheme 5a) with allyltributylstannane yields an allylpyridine.
Lemieux-Johnson oxidation (Pappo, R.; Allen, D. S. Jr.; Lemieux, R. U.;
Johnson, W. S. J. Org. Chem. 1956, 21, 478-479) of this olefin leads to
an aldehyde, from which an α,β-unsaturated ester results by
Wittig reaction. Reduction of this ester to the allylic alcohol is
effected by diisobutylaluminum hydride, and asymmetric cyclopropanation
as in preceding schemes then furnishes the cyclopropane. Deprotection of
this intermediate with acid produces the title compound.

[0996] This compound is made according to Scheme 9 by a procedure that is
very similar to that detailed in Example 8, with the exception that
butylboronic acid N,N,N',N'-tetramethyl-D(+)-tartaric acid diamide ester
((R,R)-configuration) is used in place of its (S,S)-enantiomer.

10. Synthesis of
3-[3-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol and
3-[4-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol

[0997] The requisite 3-(iodophenyl)-1-propanols were prepared according to
Scheme 10a.

##STR00131##

[0998] 3-(3-Aminophenyl)propionic acid and 3-(4-aminophenyl)propionic acid
were prepared from the appropriate regioisomers of nitrophenylcinnamic
acid following the procedure of Carnazzi et al. (J. Med. Chem. 1994, 37,
1841-1849), with the modification that hydrogen was admitted to the
reaction mixture via a balloon. The compounds were subsequently
transformed into 3-(3-iodophenyl)-1-propanol and
3-(4-iodophenyl)-1-propanol through a sequence of
diazotization/iodination and carboxyl reduction with borane as described
by Xin et al. (U.S. Patent Publication No. 2004/0167188 A1, Aug. 26,
2004, p. 21) for the meta isomer.

##STR00132##

[0999] The N-Boc protected precursors of the title compounds were prepared
according to Scheme 10b. Stille coupling of
3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine
(Scheme 5a) with hexamethyldistannane resulted in the pyridylstannane,
from which the biaryls and were obtained via a second Stille coupling
reaction with the iodophenylpropanols of Scheme 10a.

##STR00133##

[1000] The title compounds were prepared from their N-Boc-protected
precursors by deprotection with trifluoroacetic acid as shown in Scheme
10c. To transform the initially obtained trifluoroacetates into the
hydrochlorides, the free bases were prepared via ion exchange and then
neutralized with HCl.

[1002] 3-[3-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]-5-fluorophenyl]-1-pro-
panol is prepared according to Scheme 11. Commercially available
3-fluoro-5-iodobenzaldehyde is chain-extended to the cinnamate by
Knoevenagel condensation with monomethyl malonate (Yang, Z. et al., J.
Org. Chem. 1992, 57, 7248-7257). Alternatively, the Wadsworth-Emmons
reaction may be used. Stille coupling with
3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)-
pyridine establishes the biaryl motif. The side chain is then modified by
catalytic hydrogenation of the olefinic double bond followed by ester
reduction. Finally, deprotection is effected by acid treatment (as shown,
or directly with HCl).

[1004] These compounds, as well as cognate sulfonamides and carboxamides,
are prepared as depicted in Scheme 12. A first Sonogashira coupling of
3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine
under standard conditions with trimethylsilylacetylene affords a
pyridylalkyne, which is desilylated by treatment with KOH in methanol.
Alternatively, tetra-n-butylammonium fluoride can be used. This step is
followed by a second Sonogashira coupling with m-iodobenzyl alcohol (in
an analogous fashion, the ortho and para isomer, as well as higher
homologues of any of the regioisomers, and also the three iodophenols,
can be employed). The triple bond is saturated by catalytic
hydrogenation; PtO2 is chosen as the catalyst to avoid
hydrogenolysis of the benzylic C--O bond.

[1005] Amine deprotection is accomplished by treatment with
trifluoroacetic acid, and the free amine is isolated by evaporation of
the reaction mixture and ion exchange. Addition of HCl results in the
hydrochloride.

[1006] To synthesize the analogous reverse amides or sulfonamides
(illustrated by the example of the N-(methanesulfonyl) derivative), the
OH group in the intermediate,
[3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]eth-
yl]phenyl]methanol, is first replaced by an amino group. As one of a
number of possible methods, the benzylic chloride is generated in a
one-pot reaction via the mesylate (see, for example: Smith, A. B. III;
Wan, Z. J. Org. Chem. 2000, 65, 3738). Chloride is then displaced by
azide in DMF or another dipolar-aprotic solvent, and the azide function
reduced to amine, e.g., by catalytic hydrogenation. Alternatively, the
benzylic chloride may be reacted with other N nucleophiles, such as
potassium phthalimide, in which case the amine is obtained by treatment
with hydrazine. It is also possible to directly treat
[3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]eth-
yl]phenyl]methanol with a free acidic nitrogen compound, such as HN3,
phthalimide, or tetrachlorophthalimide (Jia, Z. J. et al., Synlett 1999,
565-566) under Mitsunobu conditions (e.g., EtOOCN═NCOOEt/PPh3)
to obtain the amine precursors. In the case of the tetrachlorophthalimide
derivative, the amine is obtained under milder conditions (N2H4
or ethylenediamine) than those needed for the cleavage of the
unsubstituted phthalimide. The amine is then reacted with an appropriate
electrophile, in this case, methanesulfonyl chloride. Similarly, other
electrophiles such as benzenesulfonyl chloride, acetic anhydride,
pivaloyl chloride, benzoyl chloride, or nicotinoyl chloride, can be
employed to synthesize the respective analogs. To complete the synthesis
of the title compound, the N-Boc-precursor is deprotected as described
above, or directly by treatment with anhydrous HCl in a suitable organic
solvent (e.g., diethyl ether, dioxane, ethyl acetate, methanol, ethanol,
or mixtures thereof).

[1010] A synthesis of the title compound is depicted in Scheme 14. The
synthesis starts from (S)-2-[2-(benzyloxy)ethyl]oxirane (Mulzer, J.; de
Lasalle, P. J. Chem. Res. (S) 1983, 10). The opposite enantiomer is also
available (Liu, C.; Coward, J. K. J. Org. Chem. 1991, 56, 2262-2264;
Frick, J. A. et al., Synthesis 1992, 621-623), permitting the synthesis
of the diastereoisomer of the title compound with opposite absolute
configuration at the 2,5-positions of the tetrahydrofuran ring.
Copper-catalyzed ring-opening of the oxirane with allylmagnesium chloride
(Linstrumelle, G.; Lorne, R.; Dang, H. P. Tetrahedron Lett. 1978, 19,
4069-4072) results in an unsaturated alcohol, which is cyclized to a
tetrahydrofuran using an oxidative process (Inoki, S.; Mukaiyama, T.
Chem. Lett. 1990, 67). The hydroxyl group is replaced with bromine, and
the resulting bromide is coupled with a cuprate derived from
3-(tributylstannyl)pyridine by transmetalation first with butyllithium
(transmetalation of organostannanes with BuLi: Gilman, H.; Moore, F. W.;
Jones, R. G. J. Am. Chem. Soc. 1941, 63, 2482), then with the CuCN.2LiCl
complex (for the preparation of this soluble reagent and its use in the
transmetalation of organolithium to organocopper reagents, see, for
example: Lipshutz, B. H. et al. J. Am. Chem. Soc. 1990, 112, 4404-4410;
reaction of cyanocuprates with halides: Hamon, L.; Levisalles, J. J.
Organometal. Chem. 1983, 251, 133-138). The coupling product is
debenzylated to form an alcohol, which is then transformed into the
corresponding iodide.
3-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)-
pyridine is transmetalated to an organocopper reagent using the same
method as described above, which is then coupled with the iodide to form
the protected precursor of the title compound. Deprotection is performed
by acid treatment.

[1012] This compound is synthesized according to Scheme 15. The protected
precursor results from a cross-coupling reaction between an iodide and a
cuprate reagent. The iodide is derived by a sequence of routine reactions
from commercially available trans-cyclohexane-1,4-dicarboxylic acid. The
cuprate reagent is derived by halogen-metal exchange and transmetalation
from 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridi-
ne, which is obtained (Lin, N.-H. et al., U.S. Pat. No. 5,629,325, May 13,
1997) through a Mitsunobu reaction in the same manner as its azetidine
homologue (see Scheme 5a). Alcohol and amine deprotection lead to the
target compound.

[1014] Thiol ester analogs are prepared as shown in Scheme 16. While the
depicted starting material,
[trans-4-[[5-[(2(S)-pyrrolidinyl)methoxy]-3-pyridyl]methyl]cyclohexyl]met-
hanol itself is also useful in the preparation of such compounds, the
scheme shows the preparation of their next-higher homologs. The method of
homologation is the same as that shown in Scheme 2 (Swern oxidation being
depicted rather than Des s-Martin oxidation, which is also applicable).
Introduction of the thiol ester function is effected by nucleophilic
substitution performed on a derivative of the homologated alcohol, such
as its mesylate (other derivatives such as the bromide, iodide, or other
sulfonates also may be employed in this step), by the anion of the
appropriate thiocarboxylic acid, which in the depicted case is
m-fluorobenzenethioic acid. Thiocarboxylic acids can be synthesized from
carboxylic acids using a variety of methods, such as treatment with
P4S10 in the presence of a catalytic amount of Ph3SbO
(Nomura, R.; Miyazaki, S.-I.; Nakano, T.; Matsuda, H. Chem. Ber. 1990,
123, 2081-2082) or by initial formation of an imidazolide with
carbonyldiimidazole, followed by reaction of this intermediate with
H2S (McKervey, M. A.; O'Sullivan, M. B.; Myers, P. L.; Green, R. H.
J. Chem. Soc., Chem. Commun. 1993, 94-96).

[1015] An alternative route from the vinylcyclohexane intermediate to the
N-Boc-precursor of the final product is provided by the direct addition
of m-fluorobenzenethioic acid to the olefinic double bond under
free-radical conditions [cat. dibenzoyl peroxide or
azobis(isobutyronitrile), heat or irradiation; for example, Motesharei,
K.; Myles, D. C. J. Am. Chem. Soc. 1994, 116, 7413-7414].

[1017] This compound is synthesized as shown in Scheme 17. The amino group
of commercially available 3-amino-5-bromopyridine is protected with a
benzyloxycarbonyl (Cbz) group. The resulting intermediate is deprotonated
and alkylated with the mesylate derived from
N-(tert-butoxycarbonyl)-2(S)-azetidinylmethanol. From the product thus
obtained, the pyridylstannane is prepared by Stille coupling with
Me6Sn2.

[1018] Commercially available m-bromophenethyl alcohol is O-benzylated and
the derived aryllithium reacted with paraformaldehyde or 1,3,5-trioxane
to produce the substituted benzyl alcohol, from which the bromide is
prepared.

[1019] The building blocks obtained in the preceding two paragraphs are
combined through another Stille coupling reaction. In the following step,
selective hydrogenolysis of the Cbz protecting group without affecting
the benzyl ether occurs in presence of NH4OAc (Sajiki, H.
Tetrahedron Lett. 1995, 36, 3465-3468). At this point, alkyl, acyl, or
sulfonyl groups can be placed on the linker nitrogen by reaction with
appropriate electrophiles. For example, reaction with acetic anhydride
yields an acetamide. The O-benzyl group is then removed by hydrogenolysis
under mildly acidic conditions, and eventually the N-Boc group removed to
arrive at the target compound.

[1021] The synthesis of target compounds containing a CH2OCH2
linker between the saturated heterocycle and the pyridine ring is shown
in Scheme 18. The required pyridine building block,
3-bromo-5-[[1-[(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]methyl]pyr-
idine, is procured through a Williamson ether synthesis performed between
the alcohol, 5-bromo-3-pyridylmethanol, and the alkylating agent,
1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl mesylate, both readily
obtainable from commercially available starting materials. Commercially
available indole-7-carboxaldehyde is transformed into the required indole
building block by N-protection, aldehyde reduction, bromide formation,
and reaction with the lithium acetylide-ethylenediamine complex (Smith,
W. N.; Beumel, O. F., Jr. Synthesis 1974, 441). The pyridine and indole
building blocks are joined through Sonogashira coupling, and the triple
bond is hydrogenated to produce the precursor protected at both the
pyrrolidine and indole nitrogens. The indole nitrogen is deprotected, and
a side chain joined at C-3 of the indole ring by gramine formation and
nucleophilic substitution with nitromethane (e.g., Hermkens, P. H. H. et
al. J. Org. Chem. 1990, 55, 3998-4006). From the resulting
3-(2-nitroethyl)indole, either the N-methylated pyrrolidine or the
N-unsubstituted pyrrolidine is obtainable by proper choice of conditions.
Thus, treatment with LiAlH4 results, after salt formation, in the
N-methylated compound. On the other hand, the nitro group may be reduced
instead by catalytic hydrogenation, and then the Boc group removed from
the pyrrolidine with acid to produce the N-unsubstituted pyrrolidine. In
this case, a carbocation scavenger (Me2S or Et3SiH) is added to
prevent attack of the tert-butyl cation formed in this step on the indole
moiety.

[1025] Alternatively, the reduction of COOH to CHO can be executed in a
single step with thexylmonochloroborane-dimethyl sulfide (Brown, H. C.;
Nazer, B.; Cha, J. S.; Sikorski, J. A. J. Org. Chem. 1986, 51, 5264-5270;
Brown, H. C.; Cha, J. S.; Yoon, N. M.; Nazer, B. J. Org. Chem. 1987, 52,
5400-5406). One-carbon chain-extension of the aldehyde to an acetylene is
carried out with dimethyl 1-diazo-2-oxopropylphosphonate (the
Bestmann-Ohira reagent). The second requisite building block,
3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-6-methylpyri-
dine, is prepared according to a procedure known in the art (Holladay, M.
W. et al., U.S. Pat. No. 6,133,253, Oct. 17, 2000), and joined to the
acetylene by means of a Sonogashira coupling reaction. The triple bond is
saturated by catalytic hydrogenation, the phthaloyl protecting group
removed with hydrazine, and the primary amine reductively methylated
before deprotection of the azetidine nitrogen leads to the target
compound.

[1028] To assemble the "right-hand" side chain, m-iodophenylacetic acid is
reduced to alcohol, OH is replaced with Br, and the bromide is reacted
with the amide anion derived from 2-pyrrolidone. The two building blocks
and are combined via Stille coupling, followed by removal of the Boc
group to arrive at the target compound.

22. General Scheme for the Synthesis of Heteroaryl Analogs by Formation of
the Pyridine-Heteroarene Bond Via Stille or Suzuki Coupling

##STR00146##

[1032] Regioselective bond formation between non-identical aromatic or
heteroaromatic rings is most commonly effected by reaction of a halogen
(or sulfonate) derivative of one (hetero-)aromatic moiety with an
organometallic derivative of the second (hetero)-aromatic moiety. In many
cases, those organometallic derivatives that are most stable or most
readily available require for their successful conversion the addition to
the reaction mixture of a catalytic amount of another metal compound
(commonly a palladium salt or complex), and sometimes a third metal
compound (cocatalyst), together with ligands (such as phosphines or
heterocycles) that fine-tune the steric and/or electronic properties of
the metal center (e.g., palladium) to which they bind, so as to produce
favorable selectivities and reaction rates. Which of the two
(hetero-)aromatics is employed in form of its halide or sulfonate and
which in form of its organometallic derivative, is usually decided by
consideration of synthetic accessibility. Among the most widely used
organometallic derivatives for the present purpose are those of tin and
boron, and their reactions with (hetero)-aryl halides and sulfonates form
subsets of more general classes of carbon-carbon bond forming reactions
known as the Stille and Suzuki coupling reactions, respectively. (Scheme
22; reviews: (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Aryl-Aryl Bond Formation One Century after the Discovery of
the Ullmann Reaction. Chem. Rev. 2002, 102, 1359-1469. (b) Miyaura, N.
(Ed.) "Cross-Coupling Reactions--A Practical Guide". Springer Verlag,
Berlin, 2002. (c) Kalinin, V. N. Carbon-Carbon Bond Formation in
Heterocycles Using Ni- and Pd-Catalyzed Reactions. Synthesis 1992,
413-432. (d) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry. A Guide for the Synthetic Chemist. Pergamon, Amsterdam etc.,
2000).

Therapeutic Uses

[1033] In accordance with the invention, pyridinyl nicotinic acetylcholine
receptor ligands are administered to an animal in need of treatment or
prevention of a condition.

[1035] In one embodiment, an effective amount of a pyridinyl nicotinic
acetylcholine receptor ligand can be used to treat or prevent any
condition treatable or preventable by desensitizing neuronal nAChR
receptors.

[1036] In another embodiment, an effective amount of a pyridinyl nicotinic
acetylcholine receptor ligand can be used to treat or prevent with fewer
or reduced side effects any condition treatable or preventable by
selectively desensitizing the α4β2 nAChR subtype.

[1037] In another embodiment, an effective amount of a pyridinyl nicotinic
acetylcholine receptor ligand can be used to treat or prevent any
condition treatable or preventable by activating neuronal nicotinic
acetylcholine receptors.

[1038] In another embodiment, an effective amount of a pyridinyl nicotinic
acetylcholine receptor ligand can be used to treat or prevent with fewer
or reduced side effects any condition treatable or preventable by
selectively activating the α4β2 nAChR subtype.

[1039] According to the invention, some of the pyridinyl nicotinic
acetylcholine receptor ligands are agonists at neuronal nicotinic
acetylcholine receptors, and some of the pyridinyl nicotinic
acetylcholine receptor ligands are antagonists at neuronal nicotinic
acetylcholine receptors. In another embodiment, pyridinyl nicotinic
acetylcholine receptor ligands are agonists at the α4β2
nicotinic acetylcholine receptor subtype. In another embodiment,
pyridinyl nicotinic acetylcholine receptor ligands are antagonists at the
α4β2 nicotinic acetylcholine receptor subtype. In another
embodiment, pyridinyl nicotinic acetylcholine receptor ligands
desensitize a neuronal nicotinic acetylcholine receptor. In yet another
embodiment, pyridinyl nicotinic acetylcholine receptor ligands
desensitize the α4β2 nicotinic acetylcholine receptor subtype.

[1040] The invention also provides methods for inhibiting nAChR function
in a cell, comprising contacting a cell capable of expressing the nAChR
with an amount of a pyridinyl nicotinic acetylcholine receptor ligand
effective to inhibit nAChR function in the cell. This method can be
adapted for use in vitro as part of an assay to select compounds that may
be useful for treating or preventing a condition in an animal.
Alternatively, this method can be adapted for use in vivo, (i.e., in an
animal such as a human) by contacting a cell in the animal with an
effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.
In one embodiment, the method is useful for treating or preventing
depression in an animal in need of such treatment or prevention. The
invention also relates to methods for activating nAChR function in a
cell, comprising contacting a cell capable of expressing the nAChR with
an amount of a pyridinyl nicotinic acetylcholine receptor ligand
effective to activate nAChR function in the cell. This method can be
adapted for use in vitro as part of an assay to select compounds useful
for treating or preventing a condition in an animal. Alternatively, the
method can be adapted for use in vivo (i.e., in an animal such as a
human), by contacting a cell in the animal with an effective amount of a
pyridinyl nicotinic acetylcholine receptor ligand. In one embodiment, the
method is useful for treating or preventing neurodegenerative disorders
such as Alzheimer's disease and Parkinson's disease, age-related or
disease-related cognitive impairment, dyskinesias, Tourette's syndrome,
schizophrenia, attention-deficit hyperactivity disorder, depression,
anxiety, mood disorders, pain, methamphetamine addiction and nicotine
addiction in an animal in need of such treatment or prevention.

[1042] In some embodiments, the nicotinic acetylcholine receptor ligands
of the invention are useful for modulating the activity of a nicotinic
acetylcholine receptor. In certain embodiments, the nicotinic
acetylcholine receptor ligands of formula I are useful for modulating the
activity of a nicotinic acetylcholine receptor, wherein all variables are
the same as defined above for the compounds of formula I, and with the
proviso that when Y is a bond, R5 is not
--(CH2)rNRvRvi when Rv and Rvi are each
independently hydrogen, C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl. In
other embodiments, the nicotinic acetylcholine receptor ligands of
formulas II-IV and VII-VIII, wherein all variables are as defined above
for the compounds of formulas II-IV and VII-VIII, respectively, are
useful for modulating the activity of a nicotinic acetylcholine receptor.
In still other embodiments, the nicotinic acetylcholine receptor ligands
of formula V are useful for modulating the activity of a nicotinic
acetylcholine receptor, wherein all variables are as defined above for
the compounds of formula V, and with the proviso that when Y is a bond,
R5 is not --(CH2)rNRvRvi when both Rv and
Rvi are hydrogen, or when one of Rv and Rvi is hydrogen
and the other of Rv and Rvi is C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl. In still other embodiments, the compounds of formula VI are
useful for modulating the activity of a nicotinic acetylcholine receptor,
wherein all variables are as defined above for the compounds of formula
VI, and with the proviso that when Y is a bond and Z''' is pyridine,
R5 is not --CH2OH; or --(CH2)rNRvRvi when
both Rv and Rvi are hydrogen, or when one of Rv and
Rvi is hydrogen and the other of Rv and Rvi is C1-C6
straight chain alkyl, C3-C6 branched chain alkyl or
C3-C6 cycloalkyl.

[1043] In various embodiments, the compounds of formulas I-VIII, wherein
all variables are as defined above for the compounds of formulas I-VIII,
respectively, are useful for treating depression.

[1044] In additional embodiments, the nicotinic acetylcholine receptor
ligands of formulas I-IV and VII-VIII, wherein all variables are as
defined above for the compounds of formulas I-IV and VI-VIII,
respectively, are useful for treating or preventing a condition selected
from Alzheimer's disease, Parkinson's disease, age-related cognitive
impairment, disease-related cognitive impairment, dyskinesias, Tourette's
syndrome, schizophrenia, attention-deficit hyperactivity disorder,
depression, anxiety, mood disorders, pain, methamphetamine addiction and
nicotine addiction. In various embodiments, the compounds of formula V
are useful for treating or preventing a condition selected from
Alzheimer's disease, Parkinson's disease, age-related cognitive
impairment, disease-related cognitive impairment, dyskinesias, Tourette's
syndrome, schizophrenia, attention-deficit hyperactivity disorder,
depression, anxiety, mood disorders, pain, methamphetamine addiction and
nicotine addiction, wherein all variables are the same as defined above
for the compounds of formula V, and with the proviso that when Y is a
bond, R5 is not --(CH2)rNRvRvi when both Rv
and Rvi are hydrogen, or one of Rv and Rvi is hydrogen and
the other of Rv and Rvi is C1-C6 straight chain
alkyl, C3-C6 branched chain alkyl or C3-C6
cycloalkyl. In other embodiments, the compounds of formula VI are useful
for treating or preventing a condition selected from Alzheimer's disease,
Parkinson's disease, age-related cognitive impairment, disease-related
cognitive impairment, dyskinesias, Tourette's syndrome, schizophrenia,
attention-deficit hyperactivity disorder, depression, anxiety, mood
disorders, pain, methamphetamine addiction and nicotine addiction,
wherein all variables are the same as defined above for the compounds of
formula VI, and with the proviso that when Y is a bond and Z''' is
pyridine, R5 is not --CH2OH; or
--(CH2)rNRvRvi when both Rv and Rvi are
hydrogen, or when one of Rv and Rvi is hydrogen and the other
of Rv and Rvi is C1-C6 straight chain alkyl,
C3-C6 branched chain alkyl or C3-C6 cycloalkyl.

Therapeutic/Prophylactic Administration and Compositions of the Invention

[1045] Due to their activity, the pyridinyl nicotinic acetylcholine
receptor ligands are advantageously useful in human and veterinary
medicine. As described above, the pyridinyl nicotinic acetylcholine
receptor ligands are useful for treating or preventing a condition in an
animal in need thereof. The pyridinyl nicotinic acetylcholine receptor
ligands of the invention can be administered to any animal requiring
modulation of neuronal nicotinic acetylcholine receptors.

[1046] When administered to an animal, a pyridinyl nicotinic acetylcholine
receptor ligand can be administered as a component of a composition that
comprises a pharmaceutically acceptable carrier or excipient. The
invention compositions, which comprise a pyridinyl nicotinic
acetylcholine receptor ligand, can be administered orally. A pyridinyl
nicotinic acetylcholine receptor ligand can also be administered by any
other convenient route, for example, by infusion or bolus injection, by
absorption through epithelial or mucocutaneous linings (e.g., oral,
rectal, and intestinal mucosa, etc.) and can be administered together
with a second therapeutically active agent. Administration can be
systemic or local. Various delivery systems are known, e.g.,
encapsulation in liposomes, microparticles, microcapsules,
multiparticulates, capsules, etc., and can be used to administer a
pyridinyl nicotinic acetylcholine receptor ligand.

[1047] Methods of administration include, but are not limited to,
intradermal, intramuscular, intraperitoneal, parenteral, intravenous,
subcutaneous, intranasal, epidural, oral, sublingual, intracerebral,
intravaginal, transdermal, rectal, by inhalation, or topical,
particularly to the ears, nose, eyes, or skin. The method of
administration is left to the discretion of the practitioner. In most
instances, administration will result in the release of a pyridinyl
nicotinic acetylcholine receptor ligand into the bloodstream.

[1048] In certain embodiments, it can be desirable to introduce a
pyridinyl nicotinic acetylcholine receptor ligand into the central
nervous system by any suitable route, including intraventricular,
intrathecal, and epidural injection, and enema. Intraventricular
injection can be facilitated by an intraventricular catheter, for
example, attached to a reservoir, such as an Ommaya reservoir.

[1049] Pulmonary administration can also be employed, e.g., by use of an
inhaler or nebulizer, and formulation with an aerosolizing agent, or via
perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain
embodiments, a pyridinyl nicotinic acetylcholine receptor ligand can be
formulated as a suppository, with traditional binders and excipients such
as triglycerides.

[1050] When a pyridinyl nicotinic acetylcholine receptor ligand of the
invention is incorporated for parenteral administration by injection
(e.g., continuous infusion or bolus injection), the formulation for
parenteral administration can be in the form of a suspension, solution,
emulsion in an oily or aqueous vehicle, and such formulations can further
comprise pharmaceutically necessary additives such as one or more
stabilizing agents, suspending agents, dispersing agents, and the like. A
pyridinyl nicotinic acetylcholine receptor ligand of the invention can
also be in the form of a powder for reconstitution as an injectable
formulation.

[1051] In another embodiment, a pyridinyl nicotinic acetylcholine receptor
ligand can be delivered in a vesicle, in particular a liposome (see
Langer, Science 249:1527-1533 (1990); and Treat et al., Liposomes in the
Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).

[1053] The invention compositions can optionally comprise a suitable
amount of a pharmaceutically acceptable excipient so as to provide the
form for proper administration to the animal. Such a pharmaceutical
excipient can be a diluent, suspending agent, solubilizer, binder,
disintegrant, preservative, coloring agent, lubricant, and the like. The
pharmaceutical excipient can be a liquid, such as water or an oil,
including those of petroleum, animal, vegetable, or synthetic origin,
such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
The pharmaceutical excipient can be saline, gum acacia, gelatin, starch
paste, talc, keratin, colloidal silica, urea, and the like. In addition,
auxiliary, stabilizing, thickening, lubricating, and coloring agents can
be used. In one embodiment, the pharmaceutically acceptable excipient is
sterile when administered to an animal. Water is a particularly useful
excipient when a pyridinyl nicotinic acetylcholine receptor ligand is
administered intravenously. Saline solutions and aqueous dextrose and
glycerol solutions can also be employed as liquid excipients,
particularly for injectable solutions. Suitable pharmaceutical excipients
also include starch, glucose, lactose, sucrose, gelatin, malt, rice,
flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc,
sodium chloride, dried skim milk, glycerol, propylene glycol, water,
ethanol, and the like. The invention compositions, if desired, can also
contain minor amounts of wetting or emulsifying agents, or pH buffering
agents. Specific examples of pharmaceutically acceptable carriers and
excipients that can be used to formulate oral dosage forms are described
in the Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association (1986).

[1054] The invention compositions can take the form of solutions,
suspensions, emulsions, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any other
form suitable for use. In one embodiment, the composition is in the form
of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of
suitable pharmaceutical excipients are described in Remington's
Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed.
1995), incorporated herein by reference.

[1055] In one embodiment, the pyridinyl nicotinic acetylcholine receptor
ligands are formulated in accordance with routine procedures as a
composition adapted for oral administration to human beings. A pyridinyl
nicotinic acetylcholine receptor ligand to be orally delivered can be in
the form of tablets, capsules, gelcaps, caplets, lozenges, aqueous or
oily solutions, suspensions, granules, powders, emulsions, syrups, or
elixirs, for example. When a pyridinyl nicotinic acetylcholine receptor
ligand is incorporated into oral tablets, such tablets can be compressed
tablets, tablet triturates (e.g., powdered or crushed tablets),
enteric-coated tablets, sugar-coated tablets, film-coated tablets,
multiply compressed tablets or multiply layered tablets. Techniques and
compositions for making solid oral dosage forms are described in
Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz,
eds., 2nd ed.) published by Marcel Dekker, Inc. Techniques and
compositions for making tablets (compressed and molded), capsules (hard
and soft gelatin) and pills are also described in Remington's
Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16th ed., Mack
Publishing, Easton, Pa. 1980).

[1057] When a pyridinyl nicotinic acetylcholine receptor ligand is to be
injected parenterally, it can be, e.g., in the form of an isotonic
sterile solution. Alternatively, when a pyridinyl nicotinic acetylcholine
receptor ligand is to be inhaled, it can be formulated into a dry aerosol
or can be formulated into an aqueous or partially aqueous solution.

[1058] An orally administered pyridinyl nicotinic acetylcholine receptor
ligand can contain one or more agents, for example, sweetening agents
such as fructose, aspartame or saccharin; flavoring agents such as
peppermint, oil of wintergreen, or cherry; coloring agents; and
preserving agents, to provide a pharmaceutically palatable preparation.
Moreover, where in tablet or pill form, the compositions can be coated to
delay disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time. Selectively
permeable membranes surrounding an osmotically active driving compound
are also suitable for orally administered compositions. In these latter
platforms, fluid from the environment surrounding the capsule is imbibed
by the driving compound, which swells to displace the agent or agent
composition through an aperture. These delivery platforms can provide an
essentially zero order delivery profile as opposed to the spiked profiles
of immediate release formulations. A time-delay material such as glycerol
monostearate or glycerol stearate can also be used. Oral compositions can
include standard excipients such as mannitol, lactose, starch, magnesium
stearate, sodium saccharin, cellulose, and magnesium carbonate. In one
embodiment, the excipients are of pharmaceutical grade.

[1059] In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligand can be formulated for intravenous administration.
Typically, compositions for intravenous administration comprise sterile
isotonic aqueous buffer. Where necessary, the compositions can also
include a solubilizing agent. A pyridinyl nicotinic acetylcholine
receptor ligand for intravenous administration can optionally include a
local anesthetic such as benzocaine or prilocaine to lessen pain at the
site of the injection. Generally, the ingredients are supplied either
separately or mixed together in unit dosage form, for example, as a dry
lyophilized powder or water-free concentrate in a hermetically sealed
container such as an ampule or sachette indicating the quantity of active
agent. Where a pyridinyl nicotinic acetylcholine receptor ligand is to be
administered by infusion, it can be dispensed, for example, with an
infusion bottle containing sterile pharmaceutical grade water or saline.
Where a pyridinyl nicotinic acetylcholine receptor ligand is administered
by injection, an ampule of sterile water for injection or saline can be
provided so that the ingredients can be mixed prior to administration.

[1060] A pyridinyl nicotinic acetylcholine receptor ligand can be
administered by controlled-release or sustained-release means or by
delivery devices that are known to those in the art. Examples include,
but are not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566,
each of which is incorporated herein by reference. Such dosage forms can
be used to provide controlled- or sustained-release of one or more active
ingredients using, for example, hydroxypropylmethyl cellulose, other
polymer matrices, gels, permeable membranes, osmotic systems, multilayer
coatings, microparticles, multiparticulates, liposomes, microspheres, or
a combination thereof to provide the desired release profile in varying
proportions. Suitable controlled- or sustained-release formulations known
to those in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for oral
administration such as, but not limited to, tablets, capsules, gelcaps,
and caplets that are adapted for controlled- or sustained-release.

[1061] Controlled- or sustained-release pharmaceutical compositions can
have a common goal of improving drug therapy over that achieved by their
non-controlled or non-sustained-release counterparts. In one embodiment,
a controlled- or sustained-release composition comprises a minimal amount
of a pyridinyl nicotinic acetylcholine receptor ligand to treat or
prevent the condition or a symptom thereof in a minimum amount of time.
Advantages of controlled- or sustained-release compositions include
extended activity of the drug, reduced dosage frequency, and increased
compliance. In addition, controlled- or sustained-release compositions
can favorably affect the time of onset of action or other
characteristics, such as blood levels of the pyridinyl nicotinic
acetylcholine receptor ligand, and can thus reduce the occurrence of
adverse side effects.

[1062] Controlled- or sustained-release compositions can initially release
an amount of a pyridinyl nicotinic acetylcholine receptor ligand that
promptly produces the desired therapeutic or prophylactic effect, and
gradually and continually release other amounts of the pyridinyl
nicotinic acetylcholine receptor ligand to maintain this level of
therapeutic or prophylactic effect over an extended period of time. To
maintain a constant level of the pyridinyl nicotinic acetylcholine
receptor ligand in the body, the pyridinyl nicotinic acetylcholine
receptor ligand can be released from the dosage form at a rate that will
replace the amount of pyridinyl nicotinic acetylcholine receptor ligand
being metabolized and excreted from the body. Controlled- or
sustained-release of an active ingredient can be stimulated by various
conditions, including but not limited to, changes in pH, changes in
temperature, concentration or availability of enzymes, concentration or
availability of water, or other physiological conditions or compounds.

[1063] The amount of the pyridinyl nicotinic acetylcholine receptor ligand
that is effective for the treatment or prevention of a condition can be
determined by standard clinical techniques. In addition, in vitro and/or
in vivo assays can optionally be employed to help identify optimal dosage
ranges. The precise dose to be employed will also depend on, e.g., the
route of administration and the seriousness of the condition, and can be
decided according to the judgment of a practitioner and/or each animal's
circumstances. In other examples thereof, variations will necessarily
occur depending upon the weight and physical condition (e.g., hepatic and
renal function) of the animal being treated, the affliction to be
treated, the severity of the symptoms, the frequency of the dosage
interval, the presence of any deleterious side-effects, and the
particular compound utilized, among other things.

[1064] Suitable effective dosage amounts, however, range from about 0.01
mg/kg of body weight to about 3000 mg/kg of body weight of the animal per
day, although they are typically from about 0.01 mg/kg of body weight to
about 2500 mg/kg of body weight of the animal per day or from about 0.01
mg/kg of body weight to about 1000 mg/kg of body weight of the animal per
day. In one embodiment, the effective dosage amount is about 100 mg/kg of
body weight of the animal per day or less. In another embodiment, the
effective dosage amount ranges from about 0.01 mg/kg of body weight to
about 100 mg/kg of body weight of the animal per day of a pyridinyl
nicotinic acetylcholine receptor ligand, in another embodiment, about
0.02 mg/kg of body weight to about 50 mg/kg of body weight of the animal
per day, and in another embodiment, about 0.025 mg/kg of body weight to
about 20 mg/kg of body weight of the animal per day.

[1065] Administration can be as a single dose or as a divided dose. In one
embodiment, an effective dosage amount is administered about every 24 h
until the condition is abated. In another embodiment, an effective dosage
amount is administered about every 12 h until the condition is abated. In
another embodiment, an effective dosage amount is administered about
every 8 h until the condition is abated. In another embodiment, an
effective dosage amount is administered about every 6 h until the
condition is abated. In another embodiment, an effective dosage amount is
administered about every 4 h until the condition is abated. The effective
dosage amounts described herein refer to total amounts administered; that
is, if more than one pyridinyl nicotinic acetylcholine receptor ligand is
administered, the effective dosage amounts correspond to the total amount
administered.

[1066] Where a cell capable of expressing the nicotinic acetylcholine
receptor is contacted with a pyridinyl nicotinic acetylcholine receptor
ligand in vitro, the amount effective for inhibiting or activating the
nAChR function in a cell will typically range from about 10-12 mol/L
to about 10-4 mol/L, in one embodiment, from about 10-12 mol/L
to about 10-5 mol/L, in another embodiment, from about 10-12
mol/L to about 10-6 mol/L, and in another embodiment, from about
10-12 mol/L to about 10-9 mol/L of a solution or suspension of
a pharmaceutically acceptable carrier or excipient. In one embodiment,
the volume of solution or suspension comprising the pyridinyl nicotinic
acetylcholine receptor ligand will be from about 0.01 μL to about 1
mL. In another embodiment, the volume of solution or suspension will be
about 200 μL.

[1067] The pyridinyl nicotinic acetylcholine receptor ligand will have a
binding affinity (Ki) for the α4β2 nAChR subtype of about
1000 nM or less in one embodiment, or about 500 nM or less in another
embodiment, about 100 nM or less in another embodiment, about 50 nM or
less in another embodiment, or about 20 nM or less in another embodiment,
or about 5 nM or less in another embodiment or about 1 nM or less in
another embodiment. The binding affinity Ki can be measured in ways
known to the art, e.g., by an assay utilizing membranes from recombinant
SH-EP1 cells expressing the α4β2 nACh receptor subtype. See,
e.g., Eaton J. B. et al. (2003) Mol. Pharmacol. 64:1283-1294.

[1068] The pyridinyl nicotinic acetylcholine receptor ligand will have a
Ki for the α4β2 nAChR subtype that is at least 3-fold
lower than the Ki for any other nAChR subtype, including but not
limited to the α2β4, the α3β2, the α3β4,
the α4β4, and the α4β2* nAChR subtypes in one
embodiment, at least 100-fold lower Ki for the α4β2 nAChR
subtype than the Ki for any other nAChR subtype in another
embodiment, or at least 1000-fold lower Ki for the α4β2
nAChR subtype than the Ki for any other nAChR subtype in yet another
embodiment. In yet another embodiment, the pyridinyl nicotinic
acetylcholine receptor ligand will have a Ki for the α4β2
nAChR subtype that is at least 10,000-fold lower than the Ki for any
other nAChR subtype. In another embodiment, the pyridinyl nicotinic
acetylcholine receptor ligand will have a Ki for the α4β2
nAChR subtype that is at least 100,000-fold lower than the Ki for
any other nAChR subtype.

[1069] Typically, the pyridinyl nicotinic acetylcholine receptor ligand
will have a Ki (nM) of from about 1000 to about 0.1 for binding to
the α4β2 nAChR subtype. In one embodiment, the pyridinyl
nicotinic acetylcholine receptor ligand will have a Ki (nM) of from
about 1000 to 600. In another embodiment, the pyridinyl nicotinic
acetylcholine receptor ligands of the invention will have a Ki (nM)
of from about 600 to about 300. In another embodiment, the pyridinyl
nicotinic acetylcholine receptor ligands of the invention will have a
Ki (nM) of from about 300 to about 100. In another embodiment, the
pyridinyl nicotinic acetylcholine receptor ligands of the invention will
have a Ki (nM) of from about 100 to about 35. In another embodiment,
the pyridinyl nicotinic acetylcholine receptor ligands of the invention
will have a Ki (nM) of from about 35 to about 20. In another
embodiment, the pyridinyl nicotinic acetylcholine receptor ligands of the
invention will have a Ki (nM) of from about 20 to about 15. In
another embodiment, the pyridinyl nicotinic acetylcholine receptor
ligands of the invention will have a Ki (nM) of from about 15 to
about 10. In another embodiment, the pyridinyl nicotinic acetylcholine
receptor ligands of the invention will have a Ki (nM) of from about
10 to about 4. In another embodiment, the pyridinyl nicotinic
acetylcholine receptor ligands of the invention will have a Ki (nM)
of from about 4 to about 1. In another embodiment, the pyridinyl
nicotinic acetylcholine receptor ligands of the invention will have a
Ki (nM) of from about 1 to about 0.4. In another embodiment, the
pyridinyl nicotinic acetylcholine receptor ligands of the invention will
have a Ki (nM) of from about 0.4 to about 0.1 or less.

[1070] In some embodiments, the nicotinic acetylcholine receptor ligands
of the invention are partial agonists of nicotinic acetylcholine
receptors, and do not elicit as large a functional response at the
receptors as a full agonist, such as nicotine. In other embodiments, the
nicotinic acetylcholine receptor ligands of the invention are partial
agonists that are selective for the α4β2 receptor subtype.

[1071] Where a cell capable of expressing nicotinic acetylcholine
receptors is contacted with a pyridinyl nicotinic acetylcholine receptor
ligand in vitro, the amount effective for inhibiting or activating the
α4β2 nAChR subtype function in a cell will typically range
from about 1×10-12 mol/L to about 0.1 mol/L, in one
embodiment, from about 1×10-9 mol/L to about 0.01 mol/L, and
in another embodiment, from about 1×10-6 mol/L to about 0.001
mol/L of a pyridinyl nicotinic acetylcholine receptor ligand in a
solution or suspension of a pharmaceutically acceptable carrier or
excipient. In one embodiment, the volume of solution or suspension
comprising the pyridinyl nicotinic acetylcholine receptor ligand will be
from about 0.01 μL to about 1 mL. In another embodiment, the volume of
solution or suspension will be about 100 μL to 200 μL.

[1072] The pyridinyl nicotinic acetylcholine receptor ligands will have a
binding affinity (Ki) for the human α4β2 nAChR subtype of
about 1000 nM or less in one embodiment, or about 500 nM or less in
another embodiment, about 100 nM or less in another embodiment, about 50
nM or less in another embodiment, or about 20 nM or less in another
embodiment, or about 5 nM or less in another embodiment.

[1073] The pyridinyl nicotinic acetylcholine receptor ligands can be
assayed in vitro or in vivo for the desired therapeutic or prophylactic
activity prior to use in humans. Animal model systems can be used to
demonstrate safety and efficacy.

[1074] The invention methods for treating or preventing a condition in an
animal in need thereof can further comprise co-administering to the
animal being administered a pyridinyl nicotinic acetylcholine receptor
ligand (i.e., a first therapeutic agent) a second therapeutic agent. In
one embodiment, the second therapeutic agent is administered in an
effective amount.

[1075] An effective amount of the second therapeutic agent will be known
to the art depending on the agent. However, it is well within the skilled
artisan's purview to determine the second therapeutic agent's optimal
effective-amount range. In one embodiment of the invention, where a
second therapeutic agent is administered to an animal for treatment of a
condition (e.g., depression), the minimal effective amount of the
pyridinyl nicotinic acetylcholine receptor ligand will be less than its
minimal effective amount would be where the second therapeutic agent is
not administered. In this embodiment, the pyridinyl nicotinic
acetylcholine receptor ligand and the second therapeutic agent can act
synergistically to treat or prevent a condition.

[1076] The second therapeutic agent can be, but is not limited to, an
agent for treating or preventing pain, an agent for treating or
preventing anxiety, an agent for treating or preventing a memory
disorder, an agent for treating or preventing nicotine addiction, an
agent for treating or preventing Parkinson's disease and parkinsonism, an
agent for treating or preventing psychosis associated with schizophrenia,
an agent for treating or preventing a cognitive disorder, an agent for
treating or preventing dyskinesias, an agent for treating or preventing
depression or a mood disorder, an agent for treating or preventing
Alzheimer's disease, an agent for treating or preventing Tourette's
syndrome, an agent for treating or preventing pain, an agent for treating
or preventing attention-deficit hyperactivity disorder, or any mixture
thereof.

[1090] Examples of useful therapeutic agents for treating or preventing
pain, anxiety, a memory disorder, nicotine addiction, methamphetamine
addiction, pain, Parkinson's disease and parkinsonism, psychosis
associated with schizophrenia, a cognitive disorder, dyskinesias,
depression, anxiety, a mood disorder, Alzheimer's disease, and Tourette's
syndrome include those that are known in the art and can be selected by
those skilled in the art.

[1091] A pyridinyl nicotinic acetylcholine receptor ligand and the second
therapeutic agent combined can act either additively or synergistically
to treat the same condition, or they may act independently of each other
such that the pyridinyl nicotinic acetylcholine receptor ligand treats or
prevents a first condition and the second therapeutic agent treats or
prevents a second condition. In one embodiment, a pyridinyl nicotinic
acetylcholine receptor ligand is administered concurrently with a second
therapeutic agent as a single composition comprising an effective amount
of a pyridinyl nicotinic acetylcholine receptor ligand and an effective
amount of the second therapeutic agent. Alternatively, a composition
comprising an effective amount of a pyridinyl nicotinic acetylcholine
receptor ligand and a second composition comprising an effective amount
of the second therapeutic agent are concurrently administered. In another
embodiment, an effective amount of a pyridinyl nicotinic acetylcholine
receptor ligand is administered prior or subsequent to administration of
an effective amount of the second therapeutic agent. In this embodiment,
the pyridinyl nicotinic acetylcholine receptor ligand is administered
while the second therapeutic agent exerts its therapeutic effect, or the
second therapeutic agent is administered while the pyridinyl nicotinic
acetylcholine receptor ligand exerts its therapeutic effect for treating
or preventing a condition.

[1092] A composition of the invention is prepared by a method comprising
admixing a pyridinyl nicotinic acetylcholine receptor ligand or a
pharmaceutically acceptable derivative thereof with a pharmaceutically
acceptable carrier or excipient. Admixing can be accomplished using
methods known for admixing a compound (or derivative) and a
pharmaceutically acceptable carrier or excipient. In one embodiment, the
pyridinyl nicotinic acetylcholine receptor ligand is present in the
composition in an effective amount.

Kits

[1093] The invention further provides kits that can simplify the handling
and administration of a pyridinyl nicotinic acetylcholine receptor ligand
to an animal.

[1094] A typical kit of the invention comprises a unit dosage form of a
pyridinyl nicotinic acetylcholine receptor ligand. In one embodiment, the
unit dosage form comprises a first container, which can be sterile,
containing an effective amount of a pyridinyl nicotinic acetylcholine
receptor ligand and a pharmaceutically acceptable carrier or excipient.
The kit can further comprise a label or printed instructions instructing
the use of the pyridinyl nicotinic acetylcholine receptor ligand to treat
or prevent a condition. The kit can further comprise a unit dosage form
of a second therapeutic agent, for example, a second container containing
an effective amount of the second therapeutic agent and a
pharmaceutically acceptable carrier or excipient. In another embodiment,
the kit comprises a container containing an effective amount of a
pyridinyl nicotinic acetylcholine receptor ligand, an effective amount of
a second therapeutic agent and a pharmaceutically acceptable carrier or
excipient. Examples of second therapeutic agents include, but are not
limited to, those listed above.

[1095] Kits of the invention can further comprise a device that is useful
for administering the unit dosage forms. Examples of such a device
include, but are not limited to, a syringe, a drip bag, a patch, an
inhaler, and an enema bag.

[1096] The following examples are set forth to assist in understanding the
invention and should not be construed as specifically limiting the
invention described and claimed herein. Such variations of the invention,
including the substitution of all equivalents now known or later
developed, that would be within the purview of those skilled in the art,
and changes in formulation or changes in experimental design, are to be
considered to fall within the scope of the invention incorporated herein.

EXAMPLES

General Chemistry Methods

[1097] All starting materials, solvents, and reagents were used as
obtained from commercial sources unless otherwise indicated. Oil pump
vacuum was generated with pumps rated for a final vacuum of at least 0.01
torr, but because of imperfect sealing and the substantial length of
vacuum tubing between the pump and the evacuated apparatus is estimated
to have been in the range of 0.1 to 1 torr. For reactions that were
performed under a controlled atmosphere, if not described otherwise in
the example, the atmosphere was exchanged by repeated evacuation and
admission of the required gas at the beginning of the procedure. Where
details are not mentioned, drying of solutions over a solid desiccant
entails (1) addition of an effective amount of the drying agent to the
solution, (2) agitation by stifling or swirling for several minutes, or
until the solution appears clear, (3) filtration from the drying agent
over a paper filter, cotton plug, or with gentle suction over a glass
frit preferably covered with a thin layer of celite, and (4) rinsing of
the filter residue with one or several small volumes of solvent. 1H
and 13C NMR spectra were recorded on a variety of instruments at the
indicated operating frequencies. 1H chemical shifts are reported in
ppm downfield from tetramethylsilane (TMS). TMS was contained in low
concentration in the deuterated solvent as the internal standard if so
indicated, or otherwise the deuterium frequency of the solvent peak was
used as a reference. 13C chemical shifts are referenced to
CDCl3 (central peak, δ=77.00 ppm) as the internal standard.
Mass spectra were measured in positive mode electrospray ionization (ESI)
or in electron impact ionization mode (EI; 70 eV, direct inlet).

Example 1

Synthesis of
(1S,2S)-2-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropylmethanol

[1098] This compound was prepared according to Schemes 1a and 1c. An
alternative route to its protected precursor is provided in Scheme 1b.
Each step is described under the appropriate sub-headings below.

[1100] A 500 mL three-necked flask was charged with sodium hydride (60%
dispersion in oil; 9.6 g, 240 mmol, 2.0 equiv.) and fitted out with stir
bar, dropping funnel, N2 balloon, and septa. The sodium hydride was
washed with hexane (2×150 mL), then anhydrous DMF (110 mL) was
added. With stifling and intermittent ice cooling, benzyl alcohol (25 mL,
240 mmol, 2.0 equiv.) was added dropwise within 105 min. The temperature
was kept high enough to permit efficient stifling and prevent excessive
frothing. After the addition was finished, the dropping funnel was rinsed
with anhydrous DMF. Stirring was continued at room temperature for 20
min. The flask was briefly opened to add 3,5-dibromopyridine (28.4 g, 120
mmol) all at once. The atmosphere was again replaced with N2, and
the reaction mixture was stirred at room temperature for 15 h. A thin
layer chromatogram (small aliquot quenched into EtOAc/H2O; silica
gel, EtOAc/hexane 15:85) taken shortly before the end of this period
demonstrated the near-absence of starting material (Rf 0.6) and the
formation of a product (Rf 0.25); benzyl alcohol was detected at
Rf 0.15. The bulk of DMF was distilled in an oil pump vacuum at a
bath temperature of 40° C. into a receiver cooled with acetone/dry
ice. Initial foaming was due to the evaporation of residual hexane. The
receiver was subsequently changed to maintain a high vacuum. The residue
was taken up in diethyl ether (300 mL) and the resulting suspension
poured into ice water (300 mL). The phases were separated, and the
aqueous phase was twice extracted with ether (100 mL each). The combined
organic phases were washed with brine (100 mL) and dried over MgSO4
(15 g). Evaporation furnished an orange-colored liquid together with a
colorless solid. After transfer into a 200 mL flask, benzyl alcohol was
distilled off in an oil pump vacuum into a -78° C. receiver. The
product began to crystallize after partial cooling, whereon methanol (60
mL) was added. Crystallization was initially allowed to proceed at room
temperature, then in the freezer overnight.

[1101] The product was isolated by suction filtration, washed with two
portions of freezer-chilled methanol (20 mL each), and dried (40°
C./oil pump) to obtain 23.2 g (73%) of light-tan crystals (mp
67-68.5° C.). The mother liquor was concentrated to a few mL,
diluted with methanol (15 mL), seeded, and placed in the freezer.
Isolation as above gave 1.7 g of a solid which upon TLC examination
revealed contamination with polar material. The second mother liquor
still contained substantial amounts of benzyl alcohol, which was removed
by evaporation into a 50 mL flask and bulb-to-bulb distillation at
80° C. in an oil pump vacuum until by visual appearance no further
distillate was formed. The dark residue (2.7 g) together with the impure
second crystal fraction was taken up in CH2Cl2 (3 mL) and
chromatographed on silica gel (25×3.8 cm, EtOAc/hexane 1:9) to
yield, after evaporation and drying, another 2.4 g (8%) of the product 2.
1H NMR (CDCl3, 300 MHz) δ 8.33 (narrow m, 2H), 7.50-7.32
(m, 6H), 5.11 (s, 2H).

[1103] A 500 mL round-bottom flask with stir bar was charged with
3-(benzyloxy)-5-bromopyridine (23.2 g, 87.8 mmol), palladium(II) acetate
(198 mg, 0.88 mmol, 0.01 equiv.), phenylurea (240 mg, 1.76 mmol, 0.02
equiv.), finely ground potassium carbonate (24.3 g, 176 mmol, 2 equiv.),
and anhydrous DMF (160 mL). n-Butyl acrylate (18.9 mL, 132 mmol, 1.5
equiv.) was added. The flask was fitted with a reflux condenser and
N2 balloon and, after exchange of the atmosphere, placed in an oil
bath and heated at 130° C. for 250 min. The initially
orange-colored reaction mixture soon turned black. After cooling,
volatiles were distilled off in an oil pump vacuum at a bath temperature
of 40° C. into a receiver cooled with acetone/dry ice. The residue
was taken up in EtOAc (100 mL) and filtered over a 1 cm layer of celite
in a coarse frit. The filtration residue was washed with two portions of
EtOAc (50 mL each). After evaporation, the residue was taken up in the
eluent (10 mL) and chromatographed on silica gel (23×5 cm,
EtOAc/hexane 2:3). Impure early and late fractions were combined,
evaporated, and again chromatographed on silica gel (24×2.5 cm,
EtOAc/hexane 1:2). All pure fractions were combined, evaporated, and
dried (40° C./oil pump) to obtain 27.5 g (100.5%, apparently
traces of solvent) of the product as a tan solid.

[1108] Upon concentration to 270 mL, the mother liquor deposited an
additional, darker-colored solid which adhered to the wall of the flask.
The liquid phase was decanted and the solid washed by decantation with
two portions of water (20 mL each). The solid was then recrystallized
from a boiling mixture of water (50 mL) and ethanol (30 mL). After
filtration (some loss due to premature crystallization), the solution was
placed in an ice bath. The second crystal crop was isolated by suction
filtration, washed with ethanol/water 1:2 (6 mL), and dried as above.
Thus was obtained an additional 1.3 g (6%) of the carboxylic acid as a
tan solid.

[1112] For small-scale preparations, the following method can also be
used: Oxalyl chloride (0.20 mL, 2.3 mmol, 2.0 equiv.) was added all at
once to a suspension of trans-3-[5-(benzyloxy)-3-pyridyl]acrylic acid
(302 mg, 1.18 mmol) in anhydrous CH2Cl2 (3 mL) in a 100 mL
round bottom flask with stir bar and drierite tube. An exotherm and
immediate gas evolution ensued. The carboxylic acid initially dissolved,
then a new precipitate appeared. After the mixture had been stirred at
room temperature for 13 min, volatiles were evaporated. The residual acid
chloride hydrochloride was evaporated with toluene (10 mL; in order to
remove residual oxalyl chloride) and then briefly dried (35° C./14
torr).

[1113] In the meantime, triethylamine (0.82 mL, 5.9 mmol, 5.0 equiv.) was
added at room temperature to a suspension of N,O-dimethylhydroxylamine
hydrochloride (230 mg, 2.36 mmol, 2.0 equiv.) in CH2Cl2 (5 mL).
After stifling at room temperature for 10 min, the suspension was cooled
in an ice bath with exclusion of moisture (drierite tube). The above
solid acid chloride hydrochloride was added portionwise in 17 min. After
each addition, a yellow to orange color appeared or intensified and then
gradually but incompletely faded. The mixture was stirred in the ice bath
for 10 min and then (to avoid mechanical losses) poured back into the 100
mL flask to which residual acid chloride hydrochloride adhered. Stirring
was continued at room temperature. After 70 min, TLC analysis (silica
gel, EtOAc) showed a major spot (Rf 0.35) together with a nonpolar
and a polar byproduct and baseline material. After 85 min, water (10 mL)
was added, and the phases were separated.

[1114] The aqueous phase was extracted with two portions of EtOAc (10 mL
each). Without drying, the combined organic phases were evaporated, and
the residue was chromatographed on silica gel (24×2.5 cm, ethyl
acetate/hexane 85:15). The product eluted very broadly, requiring approx.
900 mL of eluent. Evaporation of appropriate fractions and drying of the
residue (40° C./oil pump) delivered 270 mg (76%) of the title
compound as a slightly colored syrup.

[1116] In a 500 mL three-necked flask with magnetic stirrer, septa, and a
room temperature water bath, was placed trimethylsulfoxonium iodide (19.9
g, 90.5 mmol, 2.0 equiv.) in anhydrous DMSO (80 mL). Most of the air was
displaced from the flask by introduction of nitrogen from a tube into one
opened neck. The open neck was re-stoppered with a septum on which a
N2 balloon was placed through a needle. IMPORTANT PRECAUTION: To
prevent any spilled NaH from falling into water, the water bath was
covered tightly with aluminum foil. Sodium hydride (60% dispersion in
oil; 3.6 g, 90.5 mmol, 2.0 equiv.) was added in portions over a period of
25 min to the flask through a temporarily opened neck. After the addition
was finished, stifling was continued until H2 evolution became slow.
Two septa were removed from the flask, and one neck was fitted with a
dropping funnel containing
trans-3-[5-(benzyloxy)-3-pyridyl]-N-methoxy-N-methylacrylamide (13.5 g,
45.3 mmol) in anhydrous DMSO (40 mL; starting material needs gentle
warming to dissolve completely), which was stoppered with a septum. The
second open neck was attached to a N2 balloon by way of a three-way
stopcock, and the atmosphere was exchanged. The water bath was removed.
Stifling at room temperature for 60 min led to a milky suspension. The
solution of the starting material was added dropwise in 30 min
(insignificant exotherm). After 2 h at room temperature, a small aliquot
was quenched into ether/dilute brine for TLC analysis (silica gel,
EtOAc). Besides oil moving with the solvent front, a single spot was
detected (Rf 0.28; starting material: Rf 0.33). After 2.5 h,
the reaction mixture was poured into saturated aqueous NH4Cl
solution (500 mL), causing an exotherm, and enough ice was added to
return the mixture to room temperature. The product was extracted into
ether (3 portions of 200 mL each). The combined organic phases were
concentrated to approx. 200 mL and washed with brine (50 mL). Evaporation
yielded 16.5 g of two liquid phases (the oil from NaH forming the
smaller, second phase). TLC on silica gel with CH2Cl2/MeOH 95:5
showed the product at Rf approx. 0.45, the oil from NaH at the
solvent front, and traces of polar impurities. This residue was
chromatographed on silica gel (24×5 cm, CH2Cl2/MeOH 97:3
to remove the oil, then 95:5). The later fractions contained a polar
contaminant, but HPLC analysis indicated that its amount was too low for
concern. The product-containing fractions were pooled, evaporated, and
dried (50° C./oil pump) to yield 13.1 g (93%) of the cyclopropane
as a yellowish syrup. 1H NMR (300 MHz, CDCl3) δ 8.25 (br
s, 1H), 8.11 (s, 1H), 7.48-7.32 (m, 5H), 6.99 (narrow m, 1H), 5.13 (s,
2H), 3.71 (s, 3H), 3.26 (s, 3H), 2.55-2.38 (m, 2H), 1.68 (m, 1H), 1.31
(m, 1H). MS (EI) m/z 312 (M+, 0.6%), 281 (M+-OCH3, 1.6%),
252 [M+-N(Me)OMe, 4.4%], 221 (3.8%), 91 (100%).

(±)-trans-2-[5-(Benzyloxy)-3-pyridyl]cyclopropylmethanol

##STR00153##

[1118] A 500 mL flask equipped with two-neck adapter, stir bar, N2
balloon, and septum was charged with a solution of
(±)-trans-2-[5-(benzyloxy)-3-pyridyl]-N-methoxy-N-methylcyclopropaneca-
rboxamide (13.1 g, 41.9 mmol) in THF (150 mL, anhydrous from septum
bottle). Diisobutylaluminum hydride (1.0M in toluene, 63 mL, 1.5 equiv.)
was added dropwise from a syringe in 35 min at -78° C.
(acetone/CO2 bath). The mixture was stirred at -78° C. for 50
min, then the cold bath was allowed to thaw. At a total of 60 min after
the end of the addition, a small aliquot was quenched into
EtOAc/saturated potassium sodium tartrate solution and analyzed by TLC
(silica gel, EtOAc/hexane 3:1). Besides a strong baseline spot, the
product appeared at Rf 0.4, with no starting material (Rf 0.2)
remaining. After a total of 90 min (-55° C., yellow solution), the
cold bath was removed, and saturated potassium sodium tartrate solution
(100 mL) was added. The mixture was stirred vigorously without
temperature control for 75 min (gentle exotherm, disappearance of color).
The phases were separated, and the organic phase was twice extracted with
EtOAc (100 mL each). The combined organic phases were washed with brine
(100 mL) and dried over Na2SO4 (30 g). The drying agent was
filtered off with suction, the filtrate was evaporated (bath 30°
C.), and the residue was evaporated with toluene (30 mL) to leave a
slightly turbid yellow oil.

[1119] The residue contained in a 1 L round-bottom flask with magnetic
stirrer was taken up in methanol (200 mL). The moisture-protected
(balloon) solution was placed in an ice bath, and NaBH4 (4.75 g, 126
mmol, 3.0 equiv.) was added portionwise in 15 min. Some gas evolution
occurred, and the yellow color faded. The reaction mixture was stirred in
the ice bath. After 20 min, TLC analysis (silica gel, EtOAc) revealed the
presence of a polar product (Rf 0.25) besides a weak nonpolar spot
(Rf 0.7) and a mere trace of unreacted aldehyde. After a total of 40
min, the mixture was concentrated (bath 35° C.) to a small volume
(foaming!), and the residue was taken up in cold water (100 mL) and
extracted (CAUTION, some gas evolution) three times with EtOAc (50 mL
each). The combined organic phases were washed with brine (50 mL) and
evaporated without drying. The residue was subjected to CC on silica gel
(26×5 cm, EtOAc/hexane 2:1 until appearance of the alcohol, then
EtOAc/EtOH 10:1 for the product). The product-containing fractions were
evaporated and dried on the rotary evaporator at 50° C./oil pump
to furnish 10.1 g (94%) of a yellowish syrup. MS (EI) m/z 255 (M+,
6.1%), 91 (100%).

[1120] Further purification can be achieved by preparative HPLC. The
pre-purified alcohol (150 mg) was taken up in DMSO (1 mL), and the
solution was filtered over a cotton plug. This solution was injected in
two approximately equal portions onto a preparative HPLC column (Supelco
Discovery C18, 250×21.2 mm, 5 μm particle size) which was
operated at a flow of 12.5 mL/min with UV detection at 270 nm. Elution
was isocratic for 8 min with 20% CH3CN/H2O followed by a
gradient leading to 100% CH3CN in another 40 min. The alcohol eluted
at tR 26.5-27.4 min. Its solution was partially evaporated to remove
CH3CN, and the alcohol then extracted into three portions of
CH2Cl2 (10 and 2×5 mL). The combined organic phases were
dried over MgSO4 and evaporated. The material gradually solidified
after standing in a freezer overnight. After drying (40° C./oil
pump) there was obtained 128 mg of colorless crystals. Mp 67-69°
C. 1H NMR (CDCl3, TMS, 400 MHz) δ 8.16 (d, 1H, J=2.8 Hz),
8.03 (d, 1H, J=1.8 Hz), 7.44-7.32 (m, 5H), 6.88 (m, 1H), 5.08 (s, 2H),
3.67, 3.61 (ABq, 2H, J=11.4 Hz, low-field part d with J=6.0 Hz,
high-field part d with J=6.9 Hz), 1.89 (br, 1H, OH), 1.81 (m, 1H), 1.45
(m, 1H), 1.02-0.93 (m, 2H).

(1S,2S)-2-[5-(Benzyloxy)-3-pyridyl]cyclopropylmethanol and
(1R,2R)-2-[5-(Benzyloxy)-3-pyridyl]cyclopropylmethanol

[1121] The above racemate was resolved by preparative HPLC on the chiral
stationary phase, Chiralpak® AD (Chiral Technologies, Inc.). For
analytical separations, the column dimensions were 250×4.6 mm, the
mobile phase methanol, and the flow rate 1 mL/min. The resulting
chromatogram exhibited a separation factor of 2.4 and better than
baseline resolution. The retention times of the individual enantiomers
were 7.7 and 14.3 min, respectively. On a preparative scale, the
separation of 9.0 g of racemate yielded 4.5 g each of the enantiomers
with at least 99.8% enantiomeric excess. The (S,S)-enantiomer eluted
first; [α]D -69.3, [α]546 -83.4 (c 7.6 g/L, EtOAc).

[1122] Alternatively, supercritical fluid chromatography (SFC) resolution
of 24.0 g of racemate on Chiralpak AD-H at 40° C. with
methanol/CO2 2:3 gave 12.1 g of the first-eluting enantiomer of 100%
enantiomeric excess and 10.3 g of the second-eluting enantiomer of 99.5%
enantiomeric excess. The (S,S)-enantiomer eluted as the second peak under
these conditions; [α]D -71.1, [α]546 -85.5 (c 8.65
g/L, EtOAc).

[1123] The absolute configuration of the levorotatory enantiomer was
established as the required (S,S)-configuration by its independent
synthesis through enantioselective cyclopropanation employing the
Charette protocol (Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C.
Enantioselective Cyclopropanation of Allylic Alcohols with Dioxaborolane
Ligands: Scope and Synthetic Applications. J. Am. Chem. Soc. 1998, 120,
11943-11952), for which the stereochemical outcome is well-precedented.
The chemical yield and enantiomeric purity were, however, inadequate to
procure sufficient amounts of pure material on this route.

[1127] In a 500 mL three-necked flask with stir bar and two septa was
placed a solution of (1S,2S)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethyl
isobutyrate (2.39 g, 7.34 mmol) in EtOAc (40 mL) and methanol (80 mL), as
well as 10% Pd/C (160 mg, containing 50% water; Alfa Aesar #38305). A
H2 balloon was connected to the central neck through a three-way
stopcock, the reaction mixture was cooled in an ice bath, and the
atmosphere was exchanged. After 35 min, no reaction had taken place. The
reaction was continued at room temperature. After 1 h at rt, TLC on
silica gel (EtOAc; Rf 0.35 with tail) indicated completion of the
reaction. The atmosphere was replaced with N2 before opening the
flask, the reaction mixture was filtered from the catalyst over a
compacted cotton plug in the stem of a funnel, and the filtrate was
evaporated and dried (40° C./oil pump) to furnish 1.78 g
(nominally 103%, evidently containing MeOH) of the hydroxypyridine as a
nearly colorless glass. This product was evaporated with toluene (20 mL)
to remove MeOH, and directly used in the subsequent Mitsunobu reaction.
MS (EI) m/z 235 (M+, 6.4%), 147 (13%), 146 (58%), 124 (19%), 71
(17%), 43 (100%).

[1129] In a 50 mL side-arm flask with stir bar, septum, and Ar balloon,
tri-n-butylphosphine (2.89 mL, 11.7 mmol, 1.6 equiv.) was added dropwise
in 25 min to a solution of N,N-azodicarbonyldipiperidine (2.95 g, 11.7
mmol, 1.6 equiv.) in anhydrous toluene (25 mL). Stirring was continued at
room temperature for 35 min to result in a light-orange solution of the
Mitsunobu reagent. In the meantime, crude
(1S,2S)-2-(5-hydroxy-3-pyridyl)cyclopropylmethyl isobutyrate (1.78 g as
weighed after the initial evaporation, no more than 7.34 mmol due to
residual solvent content) and
1-(tert-butoxycarbonyl)-(2S)-azetidinylmethanol (2.20 g, 11.7 mmol, 1.6
equiv.) were placed in a 300 mL round-bottom flask equipped with two-neck
adapter, septum, and an Ar balloon. The starting materials were dissolved
in anhydrous toluene (25 mL), and the solution was cooled in an ice bath.
The Mitsunobu reagent was taken up in a syringe and added dropwise in 40
min. A precipitate began to form after addition of approx. one third of
the reagent, and the mixture turned highly viscous. Stirring of the
mixture at 0° C. for 80 min resulted in little conversion, whereon
the reaction was allowed to proceed at room temperature for 6 h. Shortly
before termination of the reaction, a TLC was taken (silica gel,
EtOAc/hexane 3:1). The product was observed at Rf 0.42 (UV- and
KMnO4-active) preceded by residual
N-(tert-butoxycarbonyl)-(2S)-azetidinylmethanol (Rf 0.48,
UV-inactive, slowly staining with KMnO4 on heating). Byproducts
derived from the Mitsunobu reagent stayed near the baseline.

[1133] The sequence esterification-hydrogenolysis-Mitsunobu reaction-ester
hydrolysis has also been performed using the acetate in place of the
isobutyrate ester (see scheme below).

##STR00159##

In this case, acetic anhydride was substituted for isobutyric anhydride.
The Mitsunobu reaction was executed in 61% yield using the less reactive,
traditional Mitsunobu reagent, diethyl
azodicarboxylate/triphenylphosphine, extending the reaction period to
92.5 h at room temperature. The final hydrolysis of the acetate ester
proceeded smoothly at room temperature.

[1138] To a sample (9.35 g, 22.4 mmol, 5.0 equiv.) of
methyltriphenylphosphonium bromide/NaNH2 mixture (Sigma-Aldrich; 2.4
mmol of phosphonium salt/g) in a 250 mL three-necked flask equipped with
magnetic stirrer, 2 septa, and an Ar balloon was added at room
temperature all at once diethyl ether (freshly distilled from
Na/benzophenone; 110 mL). Upon stirring for 4 h at room temperature, the
liquid phase gradually turned and eventually remained yellow from the
Wittig reagent that was formed. The residual solid was then allowed to
settle, and as much of the solution (101 mL) as possible without
disturbing the solid was transferred with a syringe into a 250 mL
three-necked flask fitted with a magnetic stirrer, two septa, and an Ar
balloon. The solution was cooled in an ice bath.

[1139] In the meantime, a 100 mL three-necked flask with magnetic stirrer,
two septa, and an Ar balloon was charged with anhydrous CH2Cl2
(40 mL) and oxalyl chloride (0.64 mL, 7.6 mmol, 1.7 equiv.). The flask
was immersed in an acetone/CO2 bath, and the solution was stirred. A
solution of anhydrous DMSO (9.0 mmol, 2.0 equiv.) in anhydrous
CH2Cl2 (4 mL) was added dropwise in 6 min. The Swern reagent
solution was stirred at approx. -70° C. for another 13 min. A
solution of
(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl-
]cyclopropylmethanol (1.50 g, 4.49 mmol) in anhydrous CH2Cl2 (12
mL) was added in 24 min. Stirring at approx. -70° C. was continued
for another 32 min. Anhydrous triethylamine (3.8 mL, 27 mmol, 6.0 equiv.)
was added dropwise in 11 min. The reaction mixture was stirred for
another 8 min at approx. -70° C. and then allowed to warm in the
thawing cold bath to +4° C. within 105 min. The initially
colorless solution turned pinkish and deposited a small quantity of
precipitate. The mixture was subsequently stirred at room temperature for
25 min, then washed with two 40 mL portions of water, each time
back-extracting with CH2Cl2 (10 mL). The combined organic
phases, without drying, were evaporated, and the residue was rapidly
filtered over silica gel (15×3.8 cm; 400 mL ether, then 1.4 L of
EtOAc/hexane 4:1) to remove baseline impurities (Rf of product: 0.18
with EtOAc/hexane 3:1). Evaporation at 30° C. and brief drying in
an oil pump vacuum at the same temperature furnished 1.46 g of the
intermediate aldehyde as a yellowish syrup.

[1141] The oxidation of the alcohol to the aldehyde can alternatively also
be performed using
1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (the
Dess-Martin periodinane).

##STR00162##

A solution of
(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl-
]cyclopropylmethanol (3.00 g, 8.97 mmol) in CH2Cl2 (25 mL) was
treated with 3 equiv. of NaHCO3 followed by Dess-Martin periodinane
(7.60 g, 18.0 mmol, 2.0 equiv.). The solution was stirred for 2 h at room
temperature. Saturated aqueous Na2SO3 (5 mL) and NaHCO3 (5
mL) were then added, and the biphasic mixture was stirred for 15 min and
extracted with EtOAc (2×100 mL). The organic phase was washed with
brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The
resulting aldehyde was purified by CC and directly used in the next
reaction.

[1143] In a 250 mL three-necked flask equipped with magnetic stirrer, 2
septa, and an Ar balloon, cyclohexene (2.80 mL, 27.6 mmol, 7.0 equiv.)
was added at room temperature in 10 min to borane-dimethylsulfide complex
(1.38 mL, 13.8 mmol, 3.5 equiv.) in tetrahydrofuran (15 mL, freshly
distilled over Na/benzophenone). A mild exotherm occurred upon the
initial addition, followed by a slightly stronger exotherm as
dicyclohexylborane crystallized. The reagent solution was stirred at room
temperature for 80 min and then cooled with an ice bath. A solution of
3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-((1S,2R)-2-vinylcy-
clopropyl)pyridine (1.30 g, 3.93 mmol) in anhydrous THF (12 mL) was added
in 25 min. The mixture was stirred at room temperature for 250 min, after
which time it formed a turbid, colorless solution. Methanol (0.16 mL, 3.9
mmol, 1.0 equiv.) was added dropwise in 5 min (caution, H2
evolution), whereafter the mixture was stirred at room temperature for 5
min. Aqueous NaOH (3N, 11.7 mL, 35 mmol, 9 equiv.) was added (dropwise
initially until additional H2 evolution subsided). Aqueous hydrogen
peroxide (35%, 7.1 mL diluted with 0.9 mL of water, 83 mmol, 21 equiv.)
was added very cautiously and dropwise in 22 min. A vigorous exotherm was
noted during the addition of approx. the first half of the peroxide.
After completion of the addition, the mixture was placed in an oil bath
which was heated to 55° C. in 25 min and kept at this temperature
for another 60 min. The mixture was cooled to room temperature and at
this point consisted of two colorless phases. The aqueous phase, but not
the organic phase, gave a strong reaction for peroxides with KT/starch
paper after the paper was exposed to HCl fumes. The phases were
separated, the aqueous phase was extracted with five portions of EtOAc
(25 mL each), and the combined organic phases were twice washed with
brine (25 mL each). They gave at this point a negative reaction with
KT/starch paper and were evaporated. TLC (SiO2,
CH2Cl2/MeOH 95:5) showed spots at Rf 0.5, 0.4
(cyclohexanol), and 0.08 (product). The residue was chromatographed on
SiO2 (25×5 cm, CH2Cl2/MeOH 96:4 until all
cyclohexanol was eluted, 93:7 to the appearance of the product, and
finally 90:10). Evaporation of the product-containing fractions yielded
1.28 g of a yellowish glass. This material was taken up in DMSO (3 mL),
and the solution was filtered over a cotton plug. Preparative HPLC was
performed in 10 portions (Supelco Discovery C18 column,
250×21.2 mm, 5 μm particle size; UV detection at 270 nm; flow
12.5 mL/min; 0-8 min, 20% CH3CN in water, then gradient from 20 to
100% of CH3CN in water within another 40 min; runs aborted after
elution of major peak and column washed with CH3CN; tR
25.5-27.4 min). The combined product-containing eluate was partially
evaporated to remove CH3CN, and the product was extracted from the
residue with CH2Cl2 (20+3×10 mL). The solution was dried
over MgSO4 and evaporated, and the residue was dried (50°
C./oil pump) to yield 1.21 g (88%) of a colorless glass. [α]D
-107, [α]546 -128 (c 9.25 g/L, EtOAc). 1H NMR
(CDCl3, 500 MHz) δ 8.13 (d, 1H, J=2.6 Hz), 8.04 (s, 1H), 6.87
(s, 1H), 4.52 (br m, 1H), 4.31 (br, 1H), 4.14 (dd, 1H, J=2.8, 10.0 Hz),
3.94-3.88 (m, 2H), 3.83-3.77 (m, 2H), 2.41-2.33 (m, 1H), 2.33-2.25 (m,
1H) 1.80 (br m, 1H), 1.75-1.64 (m, 3H), 1.43 (s, 9H), 1.17 (m, 1H), 0.98
(dt, 1H, J(d)=8.5 Hz, J(t)=5.0 Hz), 0.91 (dt, 1H, J(d)=8.5 Hz, J(t)=5.4
Hz). MS (EI) m/z 348 (M+, 0.4%), 292 (3.5%), 192 (14%), 100 (14%),
70 (11%), 56 (64%), 41 (61%).

2-[(1R,2S)-2-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethanol
Hydrochloride from
2-[(1R,2S)-2-[5-[[1-(tert-Butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyri-
dyl]cyclopropyl]ethanol by Deprotection with HCl

2-[(1R,2S)-2-[5-[((2S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethanol
from 2-[(1R,2S)-2-[5-[[1-(tert-Butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-
-pyridyl]cyclopropyl]ethanol by Deprotection with Trifluoroacetic Acid

[1170] This compound is prepared from
(1R,2R)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethanol in the same manner
as its diastereoisomer,
(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl-
]cyclopropylmethanol, is prepared in Example 1 from
(1S,2S)-2-[5-(benzyloxy)-3-pyridyl]cyclopropylmethanol.

[1172] (1R,2R)-2-[5-[[1-(tert-Butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-p-
yridyl]cyclopropylmethanol is oxidized to the aldehyde and the aldehyde
homologated to the title compound in the same manner as described in
Example 2 for their diastereoisomers.

[1174] To solution of
3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]-5-((1R,2S)-2-vinylcyclopropy-
l)pyridine in ethyl acetate is added a catalytic amount of Pd/C. The
atmosphere is replaced with hydrogen (balloon), and the reaction mixture
is stirred at room temperature until TLC or HPLC demonstrates completion
of the reaction. To remove the catalyst, the mixture is filtered over a
pad of silica gel with ethyl acetate, and the eluate is evaporated to
yield the title compound.

[1176] To a solution of
3-[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-((1R,2R)-2-ethylcyc-
lopropyl)pyridine in MeOH is added an excess of a 2M solution of anhydrous
HCl in diethyl ether. The reaction mixture is stirred at room temperature
overnight, or until the reaction is complete, and the precipitate
isolated by filtration. If a precipitate fails to form, the mixture is
evaporated to dryness and the residue triturated with ether until
solidification occurs. The product is obtained as hydrochloride in the
form of an amorphous solid.

Example 6

Synthesis of
2-[(1S,2R)-2-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethanol

[1188] This compound is prepared according to Scheme 8. The starting
material, 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyr-
idine, was obtained as shown in Scheme 5a and as reported in U.S. Pat. No.
5,629,325 (May 13, 1997; col. 22 and 52).

[1192] 2,6-Lutidine (0.76 mL, 6.5 mmol, 2.0 equiv.), OsO4 (16 mg,
0.06 mmol, 0.02 equiv.) and NaIO4 (2.1 g, 9.6 mmol, 2.9 equiv.) were
added to a stirred solution of
3-allyl-5-[[(1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine
(1.0 g, 3.3 mmol) in THF-water (20 mL, 3:1). The reaction mixture was
stirred at 25° C. and monitored by TLC. After the reaction was
complete, water and CH2Cl2 were added. The organic layer was
separated, and the water layer was extracted three times with
CH2Cl2. The combined organic layers were washed with brine and
dried over Na2SO4. The solvents were removed, and the resulting
[5-[[(1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]acetalde-
hyde was subjected to the next reaction without further purification.

[1199] 2M anhydrous HCl in ether is added to a stirred solution of
(1R,2S)-2-[[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridy-
l]methyl]cyclopropylmethanol in dry MeOH at 0° C. The mixture is
stirred at room temperature overnight and the conversion of starting
material confirmed by TLC. The above solution is concentrated and
purified by HPLC to obtain the title compound.

[1200] This compound, an isomer of the compound of Example 8, is made
according to Scheme 9 by a procedure that is very similar to that
detailed in Example 8, with the exception that butylboronic acid
N,N,N',N'-tetramethyl-D(+)-tartaric acid diamide ester (the
R,R-enantiomer) is used in place of its S,S-enantiomer.

[1202] A solution of oxalyl chloride (2.8 mL, 33 mmol, 1.7 equiv.) in
anhydrous CH2Cl2 (120 mL) was cooled to -70° C. under
N2. Then a solution of DMSO (3.0 g, 38 mmol, 1.95 equiv.) in
anhydrous CH2Cl2 (30 mL) was added dropwise in 10 min. The
Swern reagent solution was stirred at approx. -70° C. for another
15 min. A solution of
(2S)-[5-(benzyloxy)-3-pyridyl]-(1S)-cyclopropylmethanol (5.00 g, 19.6
mmol) in anhydrous CH2Cl2 (40 mL) was added in 30 min, and
stifling was continued at -70° C. for another 32 min. Anhydrous
triethylamine (16.8 mL, 121 mmol, 6.1 equiv.) was added dropwise in 15
min. The solution was stirred for another 10 min at approx. -70°
C. and then allowed to warm to 4° C. within 2 h. The reaction was
quenched with water, the phases were separated, and the organic phase was
extracted with EtOAc. The combined organic phases were washed with brine
and dried over Na2SO4. After filtration and concentration, the
residue was chromatographed on a silica gel column with EtOAc/petroleum
ether (1:10-4:1) to give the aldehyde (4.0 g, 81%) as a yellow solid.
LC-MS (ESI) m/z 254 (M+H+).

[1206] In a 100 mL round-bottom flask, PtO2 (77 mg, 0.34 mmol, 0.05
equiv.) was added under N2 at room temperature to a solution of
3-(benzyloxy)-5-[(1S,2S)-2-(2-methoxyvinyl)cyclopropyl]pyridine (1.90 g,
6.75 mmol) in CH2Cl2 (18 mL). A H2 balloon was attached,
and the atmosphere was exchanged three times. The reaction mixture was
stirred at room temperature for 6 h, after which time TLC analysis
indicated that the starting material had disappeared completely. The
catalyst was filtered off and washed with CH2Cl2 (2×5
mL). The combined filtrates were concentrated in vacuo to yield crude
3-(benzyloxy)-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine (1.90 g)
as a yellowish oil. LC-MS (ESI) m/z 284 (M+H+).

[1212] NaH (60% dispersion in mineral oil, 526 mg, 13.2 mmol, 2.0 equiv.)
was added portionwise to a solution of
3-hydroxy-5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridine (1.27 g, 6.58
mmol) in anhydrous DMF (30 mL) at room temperature under N2. After
stirring for 1 h at room temperature,
1-(tert-butoxycarbonyl)-2(S)-(4-toluenesulfonyloxy)azetidine (2.69 g, 7.9
mmol, 1.2 equiv.) in 10 mL of DMF was added, and the resulting solution
was stirred for 4 h at 80° C. under N2. After cooling, the
reaction was quenched with saturated aqueous NH4Cl solution, and the
mixture was extracted with EtOAc (3×80 mL). The combined organic
layers were washed with brine and dried over Na2SO4. After
filtration and concentration, the residue was chromatographed on a silica
gel column with EtOAc/petroleum ether to give the product (1.81 g, 76%)
as a colorless oil. LC-MS (ESI) m/z 363 (M+H+).

[1218] 1,1'-(Azodicarbonyl)dipiperidine (316 mg, 1.25 mmol, 1.6 equiv.)
was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in
a 10 mL round-bottom flask with a side neck. The flask was equipped with
rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar
(3 times), and the flask was cooled with an ice bath. Tributylphosphine
(309 μL, 1.25 mmol, 1.6 equiv.) was added dropwise. The mixture was
warmed to room temperature and stirred for 10 min. The colorless solution
formed was then added dropwise (via syringe) to a solution of
(1S,2S)-2-(5-benzyloxy-3-pyridyl)cyclopropylmethanol (200 mg, 0.78 mmol,
1 equiv.) and phenol (118 mg, 1.25 mmol, 1.6 equiv.) in a 25 mL
round-bottom flask (equipped with a magnetic stirrer and an Ar balloon,
and cooled with an ice bath). The resulting mixture was warmed to room
temperature and stirred overnight. The reaction was quenched by addition
of saturated NaHCO3 solution (10 mL), and the mixture was extracted
with EtOAc (3×20 mL). The combined organic phases were
concentrated, and the residue was purified by CC on SiO2
(25×2.5 cm, EtOAc/hexanes 2:1) to give the crude phenyl ether as a
white solid (248 mg, 96%), which was used for next step without further
purification. MS (EI) m/z 331 (M+, 0.2%).

5-[(1S,2S)-2-(Phenoxymethyl)cyclopropyl]-3-pyridinol

##STR00196##

[1220] To a solution of
3-(benzyloxy)-5-[(1S,2S)-2-(phenoxymethyl)cyclopropyl]pyridine (248 mg,
0.75 mmol) in EtOAc (10 mL) and methanol (5 mL) was added 10% palladium
on carbon (25 mg). The atmosphere was exchanged with H2 (3 times),
and the mixture was stirred under H2 (balloon) for 2 h. The
resulting mixture was filtered through a cotton plug, and the filtrate
was concentrated. The residue was purified by CC on SiO2
(38×1.0 cm, EtOAc/hexanes 7:3) to give the pyridinol as a colorless
solid (151 mg, 83%). MS (EI) m/z 241 (M+, 0.7%).

[1222] 1,1'-(Azodicarbonyl)dipiperidine (253 mg, 1.00 mmol, 1.6 equiv.)
was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in
a 10 mL round-bottom flask with a side neck. The flask was equipped with
rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar
(3 times), and the flask was cooled with an ice bath. Tributylphosphine
(248 μL, 1.00 mmol, 1.6 equiv.) was added dropwise. The mixture was
warmed to room temperature and was stirred for 10 min. The colorless
solution formed was then transferred dropwise (via syringe) with ice
cooling into a solution of
1-(tert-butoxycarbonyl)-2(R)-azetidinylmethanol (188 mg, 1.00 mmol, 1.6
equiv.) and 5-[(1S,2S)-2-(phenoxymethyl)cyclopropyl]-3-pyridinol (151 mg,
626 μmol) in a 25 mL round-bottom flask equipped with a magnetic
stirrer and an Ar balloon. The resulting mixture was warmed to room
temperature and stirred overnight. The reaction was quenched by addition
of saturated NaHCO3 solution (10 mL). The product was extracted into
EtOAc (3×20 mL). The combined organic phases were dried over
Na2SO4 and concentrated. The residue was purified by CC on
SiO2 (25×2.5 cm, EtOAc/hexanes 2:1) to give the crude product,
which was further purified by preparative HPLC in two portions (Supelco
Discovery C18, 250×21.2 mm, 5 μm particle size, UV
detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100%
CH3CN in water within 40 min, then 100% CH3CN for 20 min;
tR 29.1-31.1 min) to give the title compound as a yellowish oil (231
mg, 90%). MS (EI) m/z 410 (M+, 0.1%).

[1226] 1,1'-(Azodicarbonyl)dipiperidine (237 mg, 0.94 mmol, 1.6 equiv.)
was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in
a 10 mL round-bottom flask with a side neck. The flask was equipped with
rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar
(3 times), and the flask was cooled with an ice bath.
Tri-n-butylphosphine (232 μL, 0.94 mmol, 1.6 equiv.) was added
dropwise. The mixture was warmed to room temperature and stirred for 10
min. The resulting colorless solution was then added dropwise (via
syringe) with ice cooling to a solution of
(1S,2S)-2-[(5-(benzyloxy)-3-pyridyl]cyclopropylmethanol (50 mg, 0.59
mmol) and 3-hydroxypyridine (89 mg, 0.94 mmol, 1.6 equiv.) in a 25 mL
round-bottom flask (equipped with a magnetic stirrer and an Ar balloon).
The resulting mixture was warmed to room temperature and stirred for 6 h.
Air was bubbled through the mixture with stirring for 1 h. Toluene was
evaporated, and the residue was purified by CC on SiO2 (15×1.0
cm, EtOAc) to give the crude product, which was contaminated with a
by-product, 2,5-di-(1-piperidinyl)-1,3,4-oxadiazole. This material was
further purified by preparative HPLC in two portions (Supelco Discovery
C18, 250×21.2 mm, 5 μm particle size, UV detection at 270
nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water
within 40 min, then 100% CH3CN for 20 min; tR 22.7-24.0 min) to
give a yellowish oil (125 mg, 64%). MS (EI) m/z 332 (M+, 67%).

5-[(1S,2S)-2-[(3-Pyridyloxy)methyl]cyclopropyl]-3-pyridinol

##STR00200##

[1228] To a solution of
3-(benzyloxy)-5-[(1S,2S)-2-[(3-pyridyloxy)methyl]cyclopropyl]pyridine
(125 mg, 376 μmol) in EtOAc (10 mL) and methanol (5 mL) was added 10%
palladium on carbon (25 mg). The atmosphere was exchanged with H2 (3
times), and the mixture was stirred under H2 for 2 h. The resulting
mixture was filtered through a cotton plug, and the filtrate was
concentrated. The residue was evaporated with EtOAc (3×5 mL) to
give the pyridinol as a light-yellow oil, which turned in to a colorless
solid during storage (92 mg, quantitative). MS (EI) m/z 242 (M+,
14%).

[1236] To a solution of
3-(benzyloxy)-5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]pyridine (210 mg,
608 μmol) in EtOAc (10 mL) and methanol (5.0 mL) was added 10%
palladium on carbon (42 mg). The atmosphere was exchanged with H2 (3
times), and the mixture was stirred under H2 for 4 h. The resulting
mixture was filtered through a cotton plug, and the filtrate was
concentrated and azeotroped with toluene (3×5 mL) to give
5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]-3-pyridinol as a light-yellow
oil (131 mg, 84%).

[1237] 1,1'-(Azodicarbonyl)dipiperidine (207 mg, 0.82 mmol, 1.6 equiv.)
was dissolved in 2.0 mL of toluene (dried with molecular sieve 3 Å)
in a 10 mL round-bottom flask with a side neck. The flask was equipped
with rubber septa and a magnetic stirrer. The atmosphere was exchanged
with Ar (3 times), and the flask was cooled with an ice bath.
Tributylphosphine (203 μL, 0.82 mmol, 1.6 equiv.) was added dropwise.
The mixture was warmed to room temperature and stirred for 10 min. The
resulting colorless solution was then added dropwise (via syringe) with
ice cooling to a solution of
5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]-3-pyridinol (131 mg, 0.51
mmol) and 1-(tert-butoxycarbonyl)-2(S)-azetidinylmethanol (154 mg, 0.82
mmol, 1.6 equiv.) in a 25 mL round-bottom flask (equipped with a magnetic
stirrer and an Ar balloon). The resulting mixture was warmed to room
temperature and stirred overnight. Air was bubbled through the mixture
for 2 h. The solvent was evaporated, and the residue was purified by CC
on SiO2 (15×1.0 cm, EtOAc) to give the crude product, which
was further purified by preparative HPLC (Supelco Discovery C18,
250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow
rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40
min, then 100% CH3CN for 20 min; tR 28.5-30.9 min) to give a
colorless oil (170 mg, 79%). MS (EI) ink 424 (M+, 0.5%).

[1243] To a solution of
3-(benzyloxy)-5-[(1S,2S)-2-[(2-pyridylmethoxy)methyl]cyclopropyl]pyridine
(181 mg, 522 μmol) in EtOAc (15 mL) and methanol (7.5 mL) was added
10% palladium on carbon (36 mg). The atmosphere was exchanged with
H2 (3 times), and the mixture was stirred under H2 for 6 h. The
resulting mixture was filtered through a cotton plug, and the filtrate
was concentrated to give the pyridinol as a colorless oil (138 mg,
quantitative). MS (EI) m/z 256 (M+, 4.6%).

15c: Synthesis of
3-[3-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol and

15d: 3-[4-[5-[(2(S)-Azetidinyl)methoxy)]-3-pyridyl]phenyl]-1-propanol

[1257] These compounds were prepared, respectively, from
3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phen-
yl]-1-propanol and
3-[4-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phen-
yl]-1-propanol according to the procedure set forth in Scheme 10c.

Synthesis of
3-[3-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]-5-fluorophenyl]-1-propanol

[1263] This compound is synthesized according to Scheme 11.

3-Fluoro-5-iodocinnamic Acid Methyl Ester

##STR00215##

[1265] 3-Fluoro-5-iodobenzaldehyde, monomethyl malonate, and a catalytic
amount of pyrrolidine are heated in pyridine. After cooling, the solvent
is distilled off in vacuo. 2N HCl and ethyl acetate are added to the
residue, and the phases are separated. The organic layer is washed with
brine and dried over Na2SO4. After evaporation, the residue is
purified by CC on silica gel with EtOAc/hexane. Evaporation of
appropriate fractions yields the title compound.

[1267] This compound is prepared by Stille coupling of
3-fluoro-5-iodocinnamic acid methyl ester and
3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)-
pyridine, using the same procedure as described above for the preparation
of 3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]p-
henyl]-1-propanol.

[1269] To a solution of
3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-5-fluo-
rocinnamic acid methyl ester in methanol is added a catalytic amount of
palladium on carbon. The mixture is stirred under 1 bar of H2
(balloon) until the reaction is completed as monitored by TLC or HPLC.
The solvent is evaporated, and the residue is filtered over silica gel
using an EtOAc/hexane mixture. Evaporation of appropriate fractions
yields the title compound.

[1271] Diisobutylaluminum hydride (DIBAL-H, 1.0M solution in toluene, 2-3
equiv.) is added dropwise at -78° C. (acetone/CO2 bath) to a
solution of
3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-5-fluo-
ropropionic acid methyl ester in anhydrous THF (same volume as DIBAL-H
solution) in a three-necked flask equipped with a stir bar, N2
balloon, septum, and glass stopper. The reaction is monitored by
quenching small aliquots into EtOAc/saturated potassium sodium tartrate
solution and TLC analysis on silica gel. After completion of the
reaction, methanol (1 mL for each 22 mL of DIBAL-H solution) is added
dropwise, resulting in H2 evolution. The cold bath is removed, and
saturated aqueous potassium sodium tartrate solution (twice the volume of
the DIBAL-H solution) is added all at once. The mixture is stirred
vigorously at room temperature for 1 h. The resulting solution or
emulsion is extracted several times with EtOAc. The combined organic
phases are washed with brine and evaporated. The residue is
chromatographed on silica gel, and the product-containing fractions are
evaporated to yield the title compound.

[1273] This compound is obtained from its precursor,
3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-5-f-
luorophenyl]-1-propanol by deprotection in an analogous manner as
described in Scheme 10c for the preparation of
3-[3-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol
hydrochloride and
3-[4-[5-[(2(S)-azetidinyl)methoxy)]-3-pyridyl]phenyl]-1-propanol
hydrochloride.

[1304] A 1.37 mmolar run, using a proportionally larger column for the
chromatographic separation of the reaction mixture, yielded only 40% of
the product. This is likely due to longer contact time of the product
with the stationary phase, by which the tetrachlorophthalimide moiety
appears to be hydrolyzed.

[1306] In a 50 mL round-bottom flask with magnetic stirrer,
N-[3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]p-
henyl]propyl]-3,4,5,6-tetrachlorophthalimide (347 mg, 522 μmol) was
dissolved in acetonitrile (2 mL), tetrahydrofuran (1 mL), and ethanol (1
mL). Ethylenediamine (157 μL, 2.35 mmol, 4.5 equiv.) was added. The
flask was equipped with a reflux condenser, three-way stopcock, and Ar
balloon, and the atmosphere was exchanged. The mixture was heated in an
oil bath at 60° C. for 160 min. The resulting yellowish solution
and fine, colorless precipitate were cooled to room temperature. TLC
(SiO2, CH2Cl2/MeOH/Et3N 90:10:5, UV detection)
demonstrated disappearance of the starting material which was replaced
with two major new spots (Rf approx. 0.5 and 0.4) besides nonpolar
byproducts. The mixture was evaporated and the residue chromatographed on
SiO2 (23×2.5 cm, CH2Cl2/MeOH/Et3N 93:7:5, then
9:1:1). Fractions containing the two major products were combined,
evaporated, and dried (50° C./oil pump vacuum) to yield 358 mg of
crude 3-[3-[5-[[1-(tert-butoxycarbonyl)-2
(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]propanamine as a yellowish,
turbid glass, which was used in the subsequent step without purification.

[1320] To a solution of
3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine (704
mg, 2.05 mmol) in CH2Cl2 (20 mL) contained in a 200 mL
round-bottom flask with magnetic stirrer was added a mixture of
CF3COOH (4 mL) and water (0.4 mL). The flask was loosely stoppered
(some pressure may otherwise build up). The mixture was stirred at room
temperature for 15.5 h, then evaporated (bath 30° C.) to leave
4.56 g of a colorless liquid. This residue was taken up in
CH2Cl2 (20 mL) and placed in a round-bottom flask with magnetic
stirrer and ice bath. Triethylamine (3.4 mL, 24.5 mmol, 12 equiv.) was
added dropwise in 5 min. After 4 min of stirring in the ice bath, benzyl
chloroformate (0.44 mL, 3.1 mmol, 1.5 equiv.) was added dropwise in 7
min. The reaction mixture was then stirred at room temperature for 3.5 h.
A thin-layer chromatogram taken after 3 h (SiO2, EtOAc/hexane 2:3;
product: Rf 0.2) indicated low conversion, most of the balance being
baseline material (amine salt; reaction mixture unexpectedly acidic by
testing with moist pH paper). After re-cooling in an ice bath, additional
triethylamine (1.7 mL, 6 equiv.) and benzyl chloroformate (0.44 mL, 1.5
equiv.) were added. The mixture was stirred at room temperature for 3 h
and then evaporated to produce a colorless sludge, which was taken up in
water (20 mL) and extracted with EtOAc (3×10 mL). The combined
organic phases were without drying evaporated, and the residue was
chromatographed on SiO2 (25×2.5 cm, EtOAc/hexane 3:7, then
2:3). The product-containing fractions were evaporated and the residue
dried (50° C./oil pump) to obtain 756 mg of a colorless glass.

[1326] 2-(3-Iodophenyl)ethanol was prepared by borane reduction of
3-iodophenylacetic acid in THF in a similar manner as outlined in Example
17, and additionally purified by CC on SiO2 with EtOAc/hexane 2:3.

[1369] Into a 50-mL 3-necked round-bottom flask under N2 was placed a
solution of 2-(4-iodophenyl)ethanol (470 mg, 1.90 mmol) in
tetrahydrofuran (10 mL). Sodium hydride (91 mg, 3.8 mmol, 1.2 equiv.) was
added at 0° C. The mixture was warmed to room temperature and
stirred at room temperature for 2 h. Benzyl bromide (272 μL, 3.9 mmol,
1.2 equiv.) and tetra-n-butylammonium bromide (61 mg, 0.19 mmol, 0.10
equiv.) were added at room temperature. The resulting solution was
stirred for 20 h at room temperature. The reaction was then quenched by
the addition of 10 mL of aqueous NH4Cl. The solution was extracted
with 3×60 mL of EtOAc, and the organic layers were combined and
washed with 50 mL of brine. After evaporation, the residue was applied
onto a silica gel column, and the product was eluted with EtOAc/petroleum
ether 1:20 to furnish 600 mg (94%) of
1-[2-(benzyloxy)ethyl]-4-iodobenzene as a white solid.

[1377] To a solution of tert-butyl 2-(3-bromophenethoxy)acetate (580 mg,
1.84 mmol) in THF/CH3OH/H2O (8/4/4 mL) was added LiOH.H2O
(232 mg, 5.5 mmol, 3.0 equiv.) at room temperature. The reaction mixture
was stirred for 2 h at room temperature. After concentration under
vacuum, the pH of the residual solution was adjusted to 2 with 1M
hydrochloric acid. The carboxylic acid was extracted into EtOAc
(3×50 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo to afford
2-(3-bromophenethoxy)acetic acid (470 mg, 99%) as a colorless oil.

[1378] A 100 mL three-necked flask was fitted with a dropping funnel,
septa and a N2 balloon. The flask was charged with a solution of
2-(3-bromophenethoxy)acetic acid (2.20 g, 8.49 mmol) in anhydrous THF (20
mL) and cooled in an ice bath. Borane-THF complex (1.0 M in THF, 17 mL, 2
equiv.) was added dropwise to the solution of the starting material in 15
min. After 3 h, the reaction was quenched by addition (cautiously at
first until H2 evolution has abated) of THF/H2O (1:1, 30 mL).
The resulting mixture was an amber solution together with a colorless
precipitate. THF was removed from the solution by partial evaporation,
and the product was extracted into ether (200 mL). The organic phase was
washed sequentially with water (20 mL) and brine (20 mL), evaporated, and
dried over Na2SO4 to afford the title product (2.00 g, 96%) as
a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.40 (s, 1H),
7.35-7.39 (m, 1H), 7.17-7.22 (m, 2H), 3.70-3.75 (m, 4H), 3.58 (t, 2H,
J=6.9 Hz), 2.90 (t, 2H, J=7.2 Hz).

[1380] To a solution of 2-(3-bromophenethoxy)ethanol (50 mg, 0.20 mmol)
and 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine
(87 mg, 0.20 mmol, 1.0 equiv.) in anhydrous toluene (3 mL) was added
bis(triphenylphosphine)palladium(II) chloride (14.3 mg, 20 μmol, 0.10
equiv.) at room temperature under N2. The reaction mixture was
heated to reflux for 24 h in an oil bath. After cooling, water was added,
and the product was extracted into EtOAc (3×50 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
vacuum. The residue was purified by CC on silica gel with EtOAc/petroleum
ether as the eluent to give the title product (52 mg, 60%) as a light
yellow oil. LC-MS (ESI) m/z 429 (M+H+).

[1385] To a solution of (S)-2-hydroxy-3-phenylpropanoic acid (4.98 g, 30.0
mmol) in 100 mL of anhydrous THF was added slowly BH3.THF complex
(90 mL, 1M in THF, 3.0 equiv.) with ice cooling under N2. The
solution was stirred overnight at room temperature, and the reaction was
quenched with water (Caution, copious H2 evolution). After
evaporation of the solvent, the residue was diluted with water and
extracted with EtOAc (3×50 mL). The combined organic layers were
dried over Na2SO4 and concentrated to afford
(S)-3-phenylpropane-1,2-diol (4.13 g, 91%) as a colorless oil. LC-MS
(ESI) m/z 153 (M+H+).

(S)-2-Benzyloxirane

##STR00268##

[1387] To a stirred solution of (S)-3-phenylpropane-1,2-diol (4.65 g, 30
mmol) and triethylamine (4.6 mL, 33 mmol) in CH2Cl2 (80 mL) at
0° C. was added p-toluenesulfonyl chloride (5.7 g, 30 mmol) under
N2. After stirring at room temperature overnight, the mixture was
poured into ice water and washed with 1M hydrochloric acid. The aqueous
phase was back-extracted with EtOAc. The combined organic layers were
washed with saturated aqueous NaHCO3 solution and brine, and dried
over Na2SO4 to give the crude tosylate. The tosylate was then
dissolved in DMF (30 mL) followed by the addition of sodium hydride (70%
oil dispersion, 1.13 g) at 0° C. under N2. After stifling at
0° C. for 2 h, TLC demonstrated complete conversion. The reaction
was quenched by addition of water, and the aqueous layer was extracted
with EtOAc (3×50 mL). The combined organic layers were dried over
anhydrous Na2SO4, the solvent was distilled off under reduced
pressure, and the crude product was purified by CC on silica gel with
EtOAc/petroleum ether 1:20 to give the epoxide (3.00 g, 75%) as a
colorless oil. LC-MS (ESI) m/z 135 (M+H+).

[1393] Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to
CH2Cl2 (8.0 mL). This mixture was added to a sample of
1-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phen-
yl]-3-phenyl-2(S)-propanol (320 mg, 0.67 mmol) in a 25 mL round-bottom
flask with magnetic stirrer under N2. After stirring at room
temperature overnight, the solution was concentrated in vacuo, the
residue was diluted with water, and the solution was basified with
saturated aqueous NaHCO3 solution and extracted with EtOAc
(3×50 mL). The combined organic layers were washed with brine and
dried over Na2SO4. After filtration and concentration, the
crude product (300 mg) was purified by preparative HPLC (column: SunFire
Prep C18, 150×19, 5 μm particle size; UV detection at 254
nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, methanol;
40-100% B in A in 8 min). The product-containing eluate was partially
evaporated under reduced pressure to remove MeOH. The residual solution
was basified with saturated aqueous NaHCO3 solution and extracted
with EtOAc (3×50 mL). The combined organic phases were washed with
brine and dried over Na2SO4. Concentration gave the free amine
(130 mg, 52%) as a yellow oil. LC-MS (ESI) m/z 375 (M+H+).

[1409] To a solution of 1-(3-bromophenyl)-3-phenyl-2(S)-propanol (365 mg,
1.25 mmol) in 15 mL of anhydrous THF was added NaH (70% dispersion in
mineral oil, 100 mg, 2.9 mmol, 2.3 equiv.) at 0° C. under N2.
The mixture was warmed to room temperature and stirred for 30 min, then
CH3I (1.75 g, 12.3 mmol, 9.8 equiv.) was added at room temperature.
The mixture was stirred overnight at room temperature. The reaction was
quenched with saturated aqueous NH4Cl solution, and the mixture was
extracted with EtOAc (3×50 mL). The combined organic phases were
washed with brine and dried over Na2SO4. After filtration and
concentration, the residue was purified by CC on silica gel with
EtOAc/petroleum ether 1:20 to provide the methyl ether (300 mg, 78%) as a
yellow oil. LC-MS (ESI) m/z 306 (M+H+).

[1413] Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to 8
mL of CH2Cl2. This mixture was added to
3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[3-(2(S)-methoxy-3-
-phenylpropyl)phenyl]pyridine (290 mg, 0.59 mmol) at 0° C. under
N2. The solution was stirred overnight at room temperature. After
concentration in vacuo, the crude product (290 mg) was purified by
preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm;
UV detection, at 254 nm; mobile phase: A, water with 0.05% CF3COOH;
B, CH3CN; 20-60% B in A in 8 min). The product-containing eluate was
partially evaporated under reduced pressure (bath 30° C.) to
remove CH3CN. The pH of the residue was adjusted to 8.0 with
saturated aqueous NaHCO3 solution, and the product was extracted
into EtOAc (3×60 mL). The combined organic phases were washed with
brine and dried over Na2SO4. After filtration and
concentration, the free amine (118 mg, 51%) was obtained as a yellow oil.
LC-MS (ESI) m/z 389 (M+H+).

[1432] In a 50 mL round-bottom flask, a solution of
3-[[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]ethyny-
l]phenylmethanol in EtOAc was hydrogenated over PtO2 with stifling at
room temperature for 6.25 h. TLC (silica gel, EtOAc/hexane 3:1) showed a
new spot (Rf 0.15) in place of the starting material (Rf 0.3),
which was accompanied by a nonpolar impurity. The solution was
concentrated and filtered over silica gel (11×1.3 cm, EtOAc).
Evaporation of the product-containing fractions gave a quantitative yield
of crude product, which by 1H NMR was shown to be a mixture of two
major components in a molar ratio of approx. 4.5-5:1.

[1433] Further purification of the product can be achieved by preparative
HPLC (acetonitrile/water gradient on C18). The product-containing
fraction is partially evaporated to remove CH3CN, and the product is
extracted into CH2Cl2. The organic phase is dried over
MgSO4 and evaporated, and the residue is dried in vacuo to yield the
purified product.

[1435] 3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridy-
l]ethyl]phenylmethanol is dissolved in a mixture of trifluoroacetic acid,
CH2Cl2, and water. The reaction is allowed to proceed at room
temperature until the starting material is no longer detected by TLC. The
solvent is evaporated, and the residue is purified by preparative HPLC
(for example, acetonitrile/water gradient on C18). The
product-containing fraction is partially evaporated to remove CH3CN,
and the product is extracted into CH2Cl2. The organic phase is
dried over MgSO4 and evaporated. The residue is taken up in methanol
and adsorbed on a cation exchange column. The column is first eluted with
methanol to remove neutral or acidic impurities (including residual
trifluoroacetic acid), then with methanolic ammonia to recover the
product as free base. After evaporation, this material is dissolved in a
small volume of methanol, neutralized with a small excess of hydrochloric
acid, diluted with water, and lyophilized to yield the product.

[1437] To a solution of
3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethy-
l]phenylmethanol, LiCl (1-4 equiv.), and 2,6-lutidine (1-2 equiv.) in DMF
is added with stifling, cooling, and exclusion of moisture
methanesulfonyl chloride (1-1.5 equiv.). The reaction mixture is stirred
at ambient or elevated temperature until the alcohol and the intermediate
mesylate have disappeared. The solvent is then distilled into a cooled
receiver in an oil pump vacuum. The residue is diluted with EtOAc and
aqueous NaHCO3 solution. The phases are separated. The organic phase
is washed with brine, dried over MgSO4, and evaporated, and the
residue is used directly in the subsequent step. A purer product is
obtained by filtration over silica gel with EtOAc or a mixture of EtOAc
with a nonpolar solvent. The product is not stable in storage and should
be carried forward promptly.

[1439] 3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridy-
l]ethyl]phenylmethyl chloride is dissolved in DMF, and sodium azide (1-4
equiv.) is added. The reaction mixture is stirred with exclusion of
moisture at ambient or elevated temperature until all starting material
has been converted. The solvent is then distilled into a cooled receiver
in an oil pump vacuum at a bath temperature of up to 40° C.
(caution should be observed not to exceed this temperature, as organic
azides may explode upon heating). The residue is diluted with EtOAc and
water, and the phases are separated. The organic phase is washed with
brine, dried over MgSO4, and evaporated, and the residue is
chromatographed on silica gel with EtOAc or a mixture of EtOAc with a
nonpolar solvent. Evaporation of the product-containing fractions and
drying yields the azide. Before the subsequent step, the azide is
preferably evaporated with toluene to remove residual EtOAc, which may
react with the amine to be prepared. In order to obtain the following
intermediate directly in a form that does not require further
purification, it may be convenient to further purify the azide by
preparative HPLC (for example, acetonitrile/water gradient on C18).

[1441] 3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridy-
l]ethyl]phenylmethyl azide is dissolved in ethanol, and a catalytic amount
of PtO2 is added. The reaction flask is attached to a H2
balloon by way of a three-way stopcock, and the atmosphere is exchanged.
The mixture is stirred at room temperature. The reaction is followed by
TLC and terminated by replacing the atmosphere with N2 when the
starting material has disappeared. The catalyst is removed by
centrifugation or filtration over a filter membrane. The solution is
evaporated and the residue used directly in the following step. If
desired, the product can be purified by CC on silica gel eluting with
CH2Cl2/methanol/Et3N or CH2Cl2/methanol/conc.
aqueous NH3, or on deactivated basic alumina with
CH2Cl2/methanol.

[1443] 3-[2-[5-[[1-(tert-Butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridy-
l]ethyl]phenylmethylamine and triethylamine (1-2 equiv.) are dissolved in
anhydrous CH2Cl2, and with exclusion of moisture and ice
cooling a solution of methanesulfonyl chloride (1-1.5 equiv.) in
CH2Cl2 is added dropwise. The mixture is stirred in the ice
bath until no more starting amine is observed, then diethanolamine
(0.2-0.7 equiv.) is added to quench the excess of methanesulfonyl
chloride. The reaction mixture is evaporated and the residue
chromatographed on silica gel with CH2Cl2/methanol. The
product-containing fractions are evaporated, and the residue is dried in
vacuo to obtain the sulfonamide.

[1445] The same procedure as for the conversion of
3-[2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethy-
l]phenylmethanol into
3-[2-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]ethyl]phenylmethanol
hydrochloride is followed in this step.

Example 37

Synthesis of 5-[5-(2(S)-Azetidinylmethoxy)-3-pyridyl]-3-isoxazolylmethanol

[1446] The synthesis of this compound was performed according to Scheme 13
as set forth in the following steps.

[1454] To a solution of
3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[(trimethylsilyl-
)ethynyl]pyridine (500 mg, 1.3 mmol) in anhydrous THF (43 mL) was added at
0° C. 1.0M tetra-n-butylammonium fluoride solution in THF (4.0 mL,
4.0 mmol). The reaction mixture was stirred at 0° C. for 2 h. The
reaction was quenched by addition of saturated aqueous NH4Cl
solution. The mixture was extracted with CH2Cl2, and the
organic phase was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by CC on SiO2 eluting with
EtOAc/hexane 1:4 to give
3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-ethynylpyridine
(470 mg, 98%).

[1464] To a solution of this intermediate (30 mg, 0.1 mmol) in anhydrous
THF (3.3 mL) was added at 0° C. 1.0M tetra-n-butylammonium
fluoride solution in THF (0.3 mL, 0.3 mmol). The reaction mixture was
stirred at 0° C. for 1 h. The reaction was quenched by adding
saturated aqueous NH4Cl solution, and the mixture was extracted with
CH2Cl2, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by CC on SiO2 with
CH2Cl2/MeOH 9:1 to give
3-[[(1-methyl-2(S)-pyrrolidinyl)methoxy]-5-ethynylpyridine (21 mg, 93%).

[1470] To a solution of
3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-i-
soxazolyl]propionic acid methyl ester (330 mg, 0.79 mmol) in 1,4-dioxane
(4 mL) was added 40 wt % solution of methylamine in H2O (2.7 mL,
31.6 mmol). The mixture was heated at 120° C. for 12 h, cooled,
and concentrated. The residue was dissolved in water and extracted with
CH2Cl2. The organic phase was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by CC on SiO2
with EtOAc/hexane 2:1 to give
N-methyl-3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyr-
idyl]-3-isoxazolyl]propionamide (217 mg, 66%).

[1473] To 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyr-
idyl]-3-isoxazolyl]propionic acid methyl ester (210 mg, 0.5 mmol) was
added pyrrolidine (1.2 mL, 15 mmol). The mixture was heated at
100° C. for 12 h, cooled, and concentrated. The residue was
dissolved in water and extracted with CH2Cl2. The organic phase
was dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by CC on SiO2 with EtOAc/hexane 1:1 to give
3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-i-
soxazolyl]-1-(1-pyrrolidinyl)-1-propanone (230 mg, 99%).

[1485] To 3-azabicyclo[3.1.0]hexane hydrochloride (Anichem, Inc., 195
Black Horse Lane, North Brunswick, N.J. 08902; 3.78 g, 31.5 mmol) in a 50
mL round-bottom flask was added diethanolamine (10.0 g, 94.5 mmol, 3.0
equiv.). The flask was equipped with a stir bar and a short path still
head with a 25 mL round-bottom flask as receiver. The mixture was heated
with a 50 mL heating mantle (at 30% power, thermometer reading of the
vapor temperature<30° C.) under reduced pressure (diaphragm
pump, approx. 14 torr). The receiver was cooled with a dry ice/acetone
bath. Drops condensing on the flask wall and the still head were driven
over into the receiver by gentle warming with a heat gun until no further
condensate was observed. The collected ice-like solid was warmed to room
temperature to give a colorless liquid. Small portions of CaH2 were
added until no more bubbles were formed. After cessation of visible gas
evolution, the flask was stoppered and left to stand at room temperature
overnight. The dried amine was distilled using the same setup as above
into a 10 mL round-bottom flask cooled with a dry ice/acetone bath to
furnish a volatile, colorless oil (2.41 g, 92%). Density 0.94 g/mL.

[1527] Palladium(II) acetate (0.05 equiv.) was added to a solution of
n-butyl acrylate (0.27 mL, 1.5 mmol, 0.50 equiv.),
1-(triisopropylsilyl)-1H-pyrrole (1.34 g, 3.00 mmol), and tert-butyl
peroxybenzoate (0.56 mL, 1.5 mmol, 0.50 equiv.), in acetic
acid/dioxane/dimethylsulfoxide (0.23/0.69/0.08 mL). The mixture was
stirred at 35° C. for 24 h, diluted with diethyl ether (200 mL)
and water (20 mL), and filtered through a plug of celite. The organic
phase was separated and washed with saturated NaHCO3 solution
(2×30 mL) and water (30 mL). The combined aqueous layers were
further extracted with CH2Cl2. The combined organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by CC (SiO2, EtOAc/petroleum ether 1:20) to
give (E)-butyl 3-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]acrylate (0.70 g,
67%) as a light-yellow oil.

[1528] To a solution of (E)-butyl
3-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]acrylate (10.0 g, 28.7 mmol) in
200 mL of THF was added tetra-n-butylammonium fluoride trihydrate (7.5 g,
23.8 mmol, 0.83 equiv.) at room temperature under N2. The solution
was stirred for 30 min at room temperature, diluted with EtOAc (500 mL),
and washed with water (2×100 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum. The residue was applied
onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:5
to afford (E)-butyl 3-(1H-pyrrol-3-yl)acrylate (4.0 g, 72%) as a light
yellow solid. LC-MS (ESI) m/z 194 (M+H+).

Butyl 3-(1H-Pyrrol-3-yl)propionate

##STR00335##

[1530] To a solution of (E)-butyl 3-(1H-pyrrol-3-yl)acrylate (2.0 g, 10.4
mmol) in 50 mL of THF was added Pd (10% on activated carbon; 0.50 g). The
solution was deoxygenated under vacuum, and H2 was introduced to the
reaction flask from a balloon. The process was repeated three times, and
the reaction mixture was stirred for 4 h at room temperature. The mixture
was filtered through celite, and the filtrate was evaporated under
reduced pressure to yield butyl 3-(1H-pyrrol-3-yl)propionate (2.0 g, 99%)
as a light-yellow oil. LC-MS (ESI) m/z 196 (M+H+).

[1541] The absolute configuration of the individual enantiomers was
established by independent synthesis of the dextrorotatory isomer from
commercially available 1-(tert-butoxycarbonyl)pyrrolidine-2(R)-carboxylic
acid ((R)--N-Boc-beta-proline) as shown below.

##STR00341##

3(R)-[3-(Benzyloxy)propyl]pyrrolidine

##STR00342##

[1543] To a solution of tert-butyl
3(R)[3-(benzyloxy)propyl]pyrrolidine-1-carboxylate (170 mg, 0.53 mmol) in
2 mL of CH2Cl2 was added CF3COOH (0.5 mL) at room
temperature under N2. The solution was stirred for 3 h at room
temperature and then concentrated under vacuum. To the residue was added
20 mL of water, and the solution was washed with 30 mL of petroleum
ether. The aqueous layer was adjusted to pH 8.0 with 2M aqueous
NaHCO3 solution. The product was extracted into CH2Cl2
(3×40 mL), and the combined organic layers were dried over
Na2SO4 and concentrated in vacuo to give the free amine (115
mg, 99%) as a yellowish oil. LC-MS (ESI) m/z 220 (M+H+).

[1555] To a solution of tert-butyl
3(S)[3-(benzyloxy)propyl]pyrrolidine-1-carboxylate (495 mg, 1.55 mmol) in
6 mL of CH2Cl2 was added CF3COOH (1.5 mL) at room
temperature under N2. The resulting solution was stirred for 3 h at
room temperature and then concentrated under vacuum. To the residue was
added 20 mL of water, and the solution was washed with 30 mL of petroleum
ether. The water layer was adjusted to pH 8.0 with 2 M aqueous
NaHCO3 solution and extracted with CH2Cl2 (3×40 mL).
The organic layers were dried over Na2SO4 and concentrated in
vacuo to give 3(S)-[3-(benzyloxy)propyl]pyrrolidine (330 mg, 97%) as a
yellowish oil. LC-MS (ESI) m/z 220 (M+H+).

[1567] A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine
(229 mg, 1.0 mmol) and cyclohexanone (86 μL, 0.83 mmol) in MeNO2
(2 mL), followed by Et3SiH (160 μL, 1.0 mmol) were added
successively to a suspension of FeCl3 (35 mg, 0.20 mmol) in
MeNO2 (3 mL) at room temperature under Ar protection. After the
mixture was stirred at rt for 112 h, the reaction was quenched by
addition of phosphate buffer (pH 7). The mixture was extracted with
CH2Cl2, and the organic layer was dried over Na2SO4.
After evaporation, the residue was purified by CC (SiO2,
hexane/EtOAc 10:1 to 6:1) to afford
1-(tert-butoxycarbonyl)-4-[2-(cyclohexyloxy)ethyl]piperidine together
with a with by-product (182 mg total) as a colorless oil. This mixture
was used in the following step without further purification.

[1583] To a suspension of lithium aluminum hydride (60 mg, 1.59 mmol, 5.0
equiv.) in THF (5 mL) was added a solution of
3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(2(S)-pyrrolidinyl)methoxy]py-
ridine (156 mg, 0.32 mmol) in THF (1 mL). The mixture was refluxed for 1.5
h and then cooled to room temperature. To a flask containing 4-5 g of
Na2SO4 was added with stifling 40-50 mL of ether followed by
the cooled reaction mixture. Water was subsequently added dropwise to
quench residual hydride. When no more gas was generated, the mixture was
filtered, and the solid phase was washed with CH2Cl2/MeOH 4:1
(100-150 mL). Solvent removal furnished crude
3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(1-methyl-2(S)-pyrrolidinyl)m-
ethoxy]pyridine (106 mg, 81%), which could be used in the following step
without further purification.

[1590] To a suspension of lithium aluminum hydride (45 mg, 1.2 mmol, 5.0
equiv.) in THF (1.5 mL) was added a solution of
3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-
-azetidinyl]methoxy]pyridine (115 mg, 0.24 mmol) in THF (0.5 mL). The
mixture was refluxed for 1 h, then cooled to room temperature. To a flask
containing 4-5 g of Na2SO4 was added with stifling 40-50 mL of
Et2O followed by the cooled reaction mixture. Water was subsequently
added dropwise to quench residual hydride. When no more gas was
generated, the mixture was filtered, and the solid phase was washed with
CH2Cl2/MeOH 4:1 (100-150 mL). Solvent removal furnished crude
3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(1-methyl-2(S)-azetidinyl)met-
hoxy]pyridine (97 mg, 100%), which was used in the following step without
purification.

[1603] To a suspension of lithium aluminum hydride (46.4 mg, 1.22 mmol, 5
equiv.) in THF (2 mL) was added a solution of
3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(R)-
-pyrrolidinyl]methoxy]pyridine (121 mg, 0.24 mmol) in THF (0.5 mL). The
resulting mixture was refluxed for 1.5 h, then cooled to room
temperature. To a flask containing 4-5 g of Na2SO4 was added
with stifling 40-50 mL of Et2O followed by the cooled reaction
mixture. Water was subsequently added dropwise to quench the reaction.
When no more gas was generated, the mixture was filtered, and the solid
phase was washed with CH2Cl2/MeOH 4:1 (100-150 mL). Solvent
removal furnished crude
3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(1-methyl-2(R)-pyrrolidinyl)m-
ethoxy]pyridine (110 mg), which could be used in the following step
without purification.

[1614] To a solution of
1-(tert-butoxycarbonyl)-4-[(phenylacetoxy)methyl]piperidine (318 mg, 0.95
mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0
mmol). The reaction mixture was stirred overnight. After evaporation, the
residue was dissolved in deionized water. EtOAc was used to wash the
aqueous layer before the pH was altered to approx. 9-10. The aqueous
layer was extracted three times with CH2Cl2 and dried over
Na2SO4. After evaporation, 4-[(phenylacetoxy)methyl]piperidine
(173 mg, 78%) was obtained as a colorless oil.

[1620] To a mixture of 4-phenyl-1-butanol (601 mg, 4.0 mmol), Ph3P
(1.57 g, 6.0 mmol, 1.5 equiv.) and imidazole (409 mg, 6.0 mmol, 1.5
equiv.) in toluene (20 mL) was added I2 (1.52 g, 6.0 mmol, 1.5
equiv.) at 0° C. The mixture was allowed to stand overnight, and
the reaction was quenched with saturated Na2S2O3 solution.
The mixture was extracted with hexane/EtOAc 10:1, and the organic layer
was washed with brine and dried over Na2SO4. After
concentration, the residue was filtrated through Celite, and the Celite
was washed with hexane. After removal of the solvent,
(4-iodobutyl)benzene (1.04 g, 100%) was obtained as a pale yellow oil,
which was used in the subsequent step without purification.

[1621] A solution of (4-iodobutyl)benzene (1.04 g, 4.0 mmol) and Ph3P
(1.05 g, 4.0 mmol) in CH3CN (20 mL) was stirred for 48 h and then
washed with hexane. The solvent was removed to afford
triphenyl(4-phenylbutyl)phosphonium iodide (1.30 g, 62%) as a white foam,
which was used in the following step without purification.

[1633] To a solution of
1-(tert-butoxycarbonyl)-4-[2-(phenylacetoxy)ethyl]piperidine (431 mg,
1.24 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0
mmol). The reaction mixture was stirred overnight. After evaporation, the
residue was dissolved in deionized water. EtOAc was used to wash the
aqueous layer before the pH was altered to approx. 9-10. The aqueous
layer was extracted three times with CH2Cl2, and the combined
organic phases were dried over Na2SO4. After evaporation,
4-[2-(phenylacetoxy)ethyl]piperidine (268 mg, 87%) was obtained as a
colorless oil.

[1634] In a oven-dried flask, 4-[2-(phenylacetoxy)ethyl]piperidine (101
mg, 0.41 mmol) and InBr3 (290 mg, 0.82 mmol, 2 equiv.) were
dissolved in toluene (2 mL). After degassing and replacement of the
atmosphere with Ar, Et3SiH (260 μL, 1.64 mmol, 4 equiv.) was
added. The mixture was stirred at 90° C. for 4 h. After cooling to
room temperature, the reaction was quenched with 1N HCl. After the
aqueous layer was washed with EtOAc, its pH was raised to 9-10. After
extraction with CH2Cl2, the organic layer was dried with
Na2SO4. The solvent was removed to afford
4-[2-(2-phenylethoxy)ethyl]piperidine (40 mg, 42%) as a colorless oil.

[1635] To a solution of
3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine
(118 mg, 0.33 mmol) and 4-[2-(2-phenylethoxy)ethyl]piperidine (77 mg,
0.33 mmol) in anhydrous toluene (2 mL) were added successively sodium
tert-butoxide (48 mg, 0.50 mmol, 1.5 equiv.),
tris(dibenzylideneacetone)dipalladium(0) (6.1 mg, 6.6 μmol, 0.02
equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos;
11.5 mg, 20 μmol, 0.06 equiv.). The mixture was degassed and purged
with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After
cooling to room temperature, the mixture was diluted with EtOAc, and the
solution was washed with brine, dried over Na2SO4, and
evaporated. The residue was purified by CC on SiO2 with
CH2Cl2/EtOAc 4:1, then 1:1.
3-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(2-phenyle-
thoxy)ethyl]-1-piperidinyl]pyridine (96 mg, 57%) was obtained as a
pale-yellow oil.

[1638] To a solution of commercially available
3-[1-(tert-butoxycarbonyl)-3-piperidinyl]propionic acid (2.57 g, 10.0
mmol) in 100 mL of anhydrous THF was added slowly a solution of
BH3.THF complex in THF (1.0 M, 20 mL, 2.0 equiv) at room temperature
under N2. The solution was stirred for 16 h at room temperature.
Water was added carefully (hydrogen evolution!), and the resulting
solution was concentrated under reduced pressure. The residue was diluted
with water and extracted with EtOAc. The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was
removed under reduced pressure to give the alcohol (2.35 g, 97%) as a
colorless oil. LC-MS (ESI) m/z 244 (M+H+).

[1644] In another variant of this method, the sequence of the borane
reduction/benzylation steps and of the enantiomer resolution by
preparative HPLC was reversed as shown below. Both enantiomers of
3-[1-(tert-butoxycarbonyl)-3-piperidinyl]propionic acid were transformed
into the enantiomeric hydrochlorides of 3-(3-piperidinyl)propionic acid,
which exhibited opposite optical rotations of equal absolute value. Of
these, the R-enantiomer was identified by the positive sign of its
optical rotation, as has been reported in the literature (Brehm, R.;
Ohnhauser, D.; Gerlach, H. Helv. Chim. Acta 1987, 70, 1981-1987). The
N-Boc precursor leading to this enantiomer was subjected to borane
reduction and benzylation to arrive at tert-butyl
3(R)-[3-(benzyloxy)propyl]piperidine-1-carboxylate which was found
dextrorotatory, whereby the

##STR00386##

assignment of R-configuration to the dextrorotatory enantiomer obtained
by resolution of racemic tert-butyl
3-[3-(benzyloxy)propyl]piperidine-1-carboxylate was confirmed.

3(S)-[3-(Benzyloxy)propyl]piperidine

##STR00387##

[1646] To a solution of tert-butyl
3(S)-[3-(benzyloxy)propyl]piperidine-1-carboxylate (280 mg, 0.84 mmol) in
CH2Cl2/H2O (6 mL/0.5 mL) was added CF3COOH (1.92 g,
16.8 mmol, 20 equiv.) at 0° C. under N2. The solution was
stirred overnight at room temperature. After concentration under reduced
pressure, water was added, and the solution was washed with hexane. The
aqueous phase was basified with saturated NaHCO3 solution and
extracted with EtOAc. The combined organic layers were washed with brine
and dried over Na2SO4. The solvent was removed in vacuo to give
3(S)-[3-(benzyloxy)propyl]piperidine (190 mg, 97%) as a yellow oil. LC-MS
(ESI) m/z 234 (M+H+).

[1648] In a 100 mL round-bottom flask under N2, a solution/suspension
of 3(S)-[3-(benzyloxy)propyl]piperidine (250 mg, 1.07 mmol),
3-bromo-5-[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]pyridine (570 mg,
1.60 mmol, 1.5 equiv.), sodium tert-butoxide (150 mg, 1.56 mmol, 1.50
equiv.), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 20 μmol,
0.02 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos; 37 mg, 60 μmol, 0.06 equiv.) in 20 mL of anhydrous toluene
was stirred for 4 h at 100° C. After this time period, the
reaction was complete as judged by TLC analysis. After concentration in
vacuo, the pH of the solution was adjusted to 5 with saturated aqueous
NH4Cl solution. The solution was extracted with EtOAc, and the
combined organic layers were washed with brine and dried. The solvent was
removed under reduced pressure. The residue was applied onto a silica gel
column, and the product was eluted with EtOAc/petroleum ether 1:10-1:1 to
give the title product (350 mg, 64%) as a yellow oil. LC-MS (ESI) m/z 510
(M+H+).

[1654] To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3(R)-carboxylic
acid (800 mg, 3.72 mmol) in 20 mL of anhydrous THF was added dropwise
BH3.THF complex (1M in THF, 7.4 mL, 2.0 equiv.) at 0° C.
under N2. The resulting solution was stirred for 4 h at room
temperature. The reaction was then quenched with water. The mixture was
concentrated under vacuum and extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The
residue was applied onto a silica gel column, which was eluted with
EtOAc/petroleum ether 1:5 to give the title compound (720 mg, 96%) as a
colorless oil. LC-MS (ESI) m/z 202 (M+H+).

[1658] To a solution of tert-butyl
3(R)-[(3-phenylpropoxy)methyl]pyrrolidine-1-carboxylate (600 mg, 1.88
mmol) in CH2Cl2 (15 mL) was added a mixture of CF3COOH
(4.62 g, 40.5 mmol, 21.6 equiv.) and water (0.3 mL) at 0° C. under
N2. The solution was stirred overnight at room temperature. After
concentration in vacuo, water was added, and the solution was washed with
hexane. The water phase was basified with saturated aqueous NaHCO3
solution and extracted with EtOAc. The combined organic phases were dried
and concentrated to obtain the product (220 mg, 53%) as a yellow oil.
LC-MS (ESI) m/z 220 (M+H+).

[1666] Into a 100-mL round-bottom flask was placed a solution of
2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethanol (1.10 g, 4.80 mmol) and
tetrabromomethane (2.40 g, 7.24 mmol, 1.86 equiv.) in tetrahydrofuran (30
mL). Triphenylphosphine (1.26 g, 4.80 mmol, 1.00 equiv.) in
CH2Cl2 was added slowly under N2 at 0° C. The
resulting solution was stirred overnight at 30° C. and then
concentrated under vacuum. The residue was applied onto a silica gel
column, which was eluted with EtOAc/petroleum ether 1:10 to 1:5. This
resulted in 1.22 g (87%) of the bromide as a colorless oil.

[1681] To a solution of
1-(tert-butoxycarbonyl)-4-[2-(4-chlorobenzyloxy)ethyl]piperidine (760 mg,
0.47 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0
mmol). The reaction mixture was stirred overnight, then evaporated, and
the residue was dissolved in deionized water. EtOAc was used to wash the
aqueous layer before the pH was altered to approx. 9-10. The aqueous
layer was extracted three times with CH2Cl2, and the combined
organic phases were dried over Na2SO4. After evaporation,
4-[2-(4-chlorobenzyloxy)ethyl]piperidine (531 mg, 97%) was obtained as a
colorless oil.

[1687] To a solution of
1-(tert-butoxycarbonyl)-4-[2-(4-fluorobenzyloxy)ethyl]piperidine (257 mg,
0.76 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (1.0 mL, 2.0
mmol). The reaction mixture was stirred overnight. After evaporation, the
residue was dissolved in deionized water. EtOAc was used to wash the
aqueous layer before the pH was altered to approx. 9-10. The aqueous
layer was extracted three times with CH2Cl2, and the combined
organic phases were dried over Na2SO4. After evaporation,
4-[2-(4-fluorobenzyloxy)ethyl]piperidine (150 mg, 83% yield) was obtained
as a colorless oil.

[1709] To a solution of 4-[2-(4-methoxybenzyloxy)ethyl]piperidine (268 mg,
0.77 mmol) in MeOH (2 mL) was added 2N anhydrous HCl/ether (0.75 mL, 1.54
mmol). The reaction mixture was stirred overnight. After evaporation, the
residue was dissolved in deionized water. EtOAc was used to wash the
aqueous layer before the pH was altered to approx. 9-10. The aqueous
layer was extracted three times with CH2Cl2 and dried over
Na2SO4. After evaporation,
4-[2-(4-methoxybenzyloxy)ethyl]piperidine (112 mg, 58%) was obtained as a
colorless oil.

[1713] All binding assays were performed according to procedures set forth
in the University of North Carolina at Chapel Hill National Institute of
Mental Health Psychoactive Drug Screening Program Assay Protocol Book
(pp. 50-54; PI: Bryan L. Roth MD, PhD).

[1715] Solutions of the compounds to be tested were prepared as a 1-mg/ml
stock in assay buffer or DMSO according to the solubility of the
compound. A similar stock solution of a reference compound (positive
control) [(-)-nicotine] was also prepared. Eleven dilutions (5×
assay concentration) of the test and reference compound were prepared in
assay buffer by serial dilution: 0.05 nM, 0.5 nM, 1.5 nM, 5 nM, 15 nM, 50
nM, 150 nM, 500 nM, 1.5 μM, 5 μM, 50 μM (thus, the corresponding
assay concentrations spanned from 10 pM to 10 μM and included semilog
points in the range where high-to-moderate affinity ligands compete with
radioligand for binding sites).

[1716] Radioligand ([3H]epibatidine) was diluted to 2.5 nM (five
times the assay concentration) in assay buffer. Aliquots (50 μl) of
radioligand were dispensed into the wells of a 96-well plate containing
100 μl of assay buffer. Then, duplicate 50-0 aliquots of the test and
reference compound dilutions were added.

[1718] The 250-μl reactions were incubated at room temperature and
shielded from light (to prevent photolysis of light-sensitive ligands)
for 4 hours, then harvested by rapid filtration onto Whatman GF/B glass
fiber filters pre-soaked with 0.5% polyethyleneimine using a 96-well
Brandel harvester. Four rapid 500-0 washes were performed with chilled
Standard Binding Buffer to reduce non-specific binding. Filters were
placed in 6-ml scintillation tubes and allowed to dry overnight. The next
day, 4 ml of EcoScint scintillation cocktail (National Diagnostics) were
added to each tube. The tubes were capped, labeled, and counted by liquid
scintillation counting.

[1719] Raw data (dpm) representing total radioligand binding (i.e.,
specific+non-specific binding) were plotted as a function of the
logarithm of the molar concentration of the competitor (i.e., test or
reference compound). Non-linear regression of the normalized (i.e.,
percent radioligand binding compared to that observed in the absence of
test or reference compound) raw data was performed in Prism 4.0
(GraphPad) using the built-in three parameter logistic model describing
ligand competition binding to radioligand-labeled sites:

y=bottom+[(top-bottom)/(1+10x-log IC50)]

where bottom is the residual radioligand binding measured in the presence
of 10 μM reference compound (i.e., non-specific binding) and top is
the total radioligand binding observed in the absence of competitor. The
log IC50 (i.e., the log of the ligand concentration that reduces
radioligand binding by 50%) was thus estimated from the data and used to
obtain the Ki by applying the Cheng-Prusoff approximation:

Ki=IC50/(1+[ligand]/KD)

where [ligand] is the assay radioligand concentration and KD is the
affinity constant of the radioligand for the target receptor.

[1722] The affinity of nicotinic acetylcholine receptor ligands for the
agonist site of the α-Bungarotoxin-insensitive nicotinic receptor
in the rat cerebral cortex were determined according to procedures set
forth in the Cerep SOP No. 1A076 (Catalog ref. 807-n1).

[1725] Non-specific binding was determined in the presence of 10 μM
nicotine.

[1726] Following incubation, the samples were filtered rapidly under
vacuum through glass fiber filters (Filtermat B, Wallac) presoaked with
0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a
48-sample cell harvester (Mach II, Tomtec). The filters were dried, then
counted for radioactivity in a scintillation counter (Betaplate 1204,
Wallac) using a solid scintillator (Meltilex B/HS, Wallac).

[1727] The specific ligand binding to the receptors is defined as the
difference between the total binding and the nonspecific binding
determined in the presence of 10 μM nicotine.

[1728] The results were expressed as a percent inhibition of the control
radioligand specific binding obtained in the presence of the test
compound: (100-((measured specific binding/control specific
binding)×100)).

[1729] The standard reference compound was nicotine, which was tested in
each experiment at several concentrations to obtain a competition curve
from which its IC50 was calculated.

[1730] The compounds whose structure appear in Examples 2, 11, 12, 14,
15c, 15d, 19, 22, 24, 27, 37, 41, 46, 49, and 51 showed greater than 50%
inhibition (ranging from 59% to 100% inhibition) of the control
radioligand specific binding at a concentration of 100 nM. The compounds
whose structure is shown in Examples 58, 62, 70, and 72, using the same
binding procedure, at a concentration of 100 nM, showed inhibition
ranging from 8% to 28%. The compound of Example 71, which is also an
intermediate that can be used to synthesize additional analogs described
herein such as the compound in Example 70, showed no binding activity at
a concentration of 100 nM.

[1735] Procedures were based on those previously described (Porsolt et
al., 1977). Mice were individually placed into clear glass cylinders
(i.e., 15 cm tall×10 cm wide, 1 L beakers) containing
23±1° C. water 12 cm deep (approximately 800 mL). The time the
animal spent immobile was recorded over a 6 min trial. Immobility was
described as the postural position of floating in the water.

[1736] Drugs.

[1737] The test compounds were AMOP--H--OH, the compounds whose structure
appear in Example 2, 4, 8, 15c, 15d, 24, 46, 49, 51, 58, 62, 72, and
sertraline (a known SSRI antidepressant). The mice were injected
intraperitoneally (i.p.) 30 minutes before the start of the test. In
another set of experiments, the test compounds were administered orally
(p.o.) 30 minutes before the start of the test. The test compounds were
the compounds whose structure appear in Examples 2, 10, 12, 15c, 24, 27,
46, 49, 51, 52, and 62.

[1738] Statistics.

[1739] The length of time spent floating was analyzed by Analysis of
Variance (ANOVA) with dose of drug as the between-subject factor and time
spent immobile across the 6 min test as the dependent variable. Post-hoc
comparisons between the treatment groups and control group were made
using Fisher's PLSD test. A significance level of 5% was used throughout.

[1740] The number of mice/group was 10 except for the vehicle group which
had 9 mice. Results marked with a double asterisk (**) are those that
were shown to be significantly different from vehicle.

[1741] AMOP--H--OH (structure shown below) showed positive effects in the
forced swim test as indicated by a reduction in immobility time (Table
2). The reference compound sertraline showed a very similar result to
that observed with AMOP--H--OH.

[1743] All groups had 10 mice. Results marked with a double asterisk (**)
are those that were shown to be significantly different from vehicle.

[1744] The compound whose structure is shown in Example 15c (structure
shown below) showed positive effects in the forced swim test as indicated
by a reduction in immobility time (Table 3 and Table 4).

[1745] All groups had 10 mice. Results marked with a double asterisk (**)
are those that were shown to be significantly different from vehicle.

[1746] The compound from Example 2, a nicotinic acetylcholine receptor
ligand of the present invention having the structure:

##STR00423##

showed positive effects in the forced swim test as indicated by a
reduction in immobility time (Table 5). The reference compound sertraline
showed a very similar result to that observed with Compound 22 (Table 5).

[1747] The compounds whose structure is shown in Examples 2, 4, 8, 15c,
15d, 24, 46, 49, 51, 58, 62, and 72 showed activity in the Forced Swim
test as indicated by an average reduction in immobility time of the mice
ranging from 22.0 to 85.7 seconds compared to the use of a vehicle that
was selected from one of water, saline or 2% pharmasolve solution, at a
dose of 10 mg/kg dose (i.p.).

[1748] The compound whose structure is shown in Examples 2, 10, 12, 24,
27, 46, 49, 51, 52, and 62 were administered p.o. in the Forced Swim test
using water as the vehicle for comparison. At a dose of 10 mg/kg (p.o.)
these compounds showed an average reduction in immobility time ranging
from 21.2 to 114.2 seconds compared to the average immobility time for
the vehicle. The compound of Example 15c at a dose of 10 mg/kg (p.o.) did
not show any change in immobility time compared to the vehicle and at a
dose of 20 mg/kg (p.o.) showed a reduction in immobility time of 24.5
seconds compared to the immobility time for the vehicle.

Patent applications by Alan P. Kozikowski, Chicago, IL US

Patent applications by Jianhua Liu, Chicago, IL US

Patent applications by Joel R. Walker, Schenectady, NY US

Patent applications by Po-Wai Yuen, Ann Arbor, MI US

Patent applications by Werner Tueckmantel, Yorktown Heights, NY US

Patent applications by Psychogenics, Inc.

Patent applications by THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS

Patent applications in class The additional hetero ring consists of one nitrogen and four carbons (e.g., nicotine, etc.)

Patent applications in all subclasses The additional hetero ring consists of one nitrogen and four carbons (e.g., nicotine, etc.)